Cyclopropyl Fused Indolobenzazepine HCV NS5B Inhibitors

ABSTRACT

The invention encompasses compounds of formula I as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.

CROSS REFERENCE TO RELATED APPLICATIONS

This Continuation application claims the benefit of U.S. Ser. No.13/778,507 filed Feb. 27, 2013, now pending, which in turn is aContinuation application of U.S. Ser. No. 13/222,256 filed Aug. 31,2011, now abandoned, which in turn is a Continuation application of U.S.Ser. No. 12/392,620 filed Feb. 25, 2009, now abandoned, which in turn isa Continuation application which claims the benefit of U.S. Ser. No.11/942,285 filed Nov. 19, 2007, now U.S. Pat. No. 7,521,443, which inturn is a Continuation-in-Part application which claims the benefit ofU.S. Ser. No. 11/743,921 filed May 3, 2007, now U.S. Pat. No. 7,456,166,which in turn is a Non-Provisional application which claims the benefitof U.S. Provisional Application Ser. Nos. 60/894,757 filed Mar. 14,2007, 60/852,084 filed Oct. 16, 2006, 60/802,005 filed May 19, 2006 and60/801,125 filed May 17, 2006, now expired.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a major human pathogen, infecting anestimated 170 million persons worldwide—roughly five times the numberinfected by human immunodeficiency virus type 1. A substantial fractionof these HCV infected individuals develop serious progressive liverdisease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.;Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the5′-untranslated region, HCV has been classified as a separate genus inthe Flaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome. At least six majorgenotypes have been characterized, and more than 50 subtypes have beendescribed. The major genotypes of HCV differ in their distributionworldwide, and the clinical significance of the genetic heterogeneity ofHCV remains elusive despite numerous studies of the possible effect ofgenotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to as NS3 protease) and mediatesall the subsequent cleavages downstream of NS3, both in cis, at theNS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions, acting as a cofactor for the NS3 protease and possiblyassisting in the membrane localization of NS3 and other viral replicasecomponents. The complex formation of the NS3 protein with NS4A seemsnecessary to the processing events, enhancing the proteolytic efficiencyat all of the sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. NS5B (also referred to asHCV polymerase) is a RNA-dependent RNA polymerase that is involved inthe replication of HCV. The HCV NS5B protein is described in “StructuralAnalysis of the Hepatitis C Virus RNA Polymerase in Complex withRibonucleotides (Bressanelli; S. et al., Journal of Virology 2002,3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7,211-242.

Currently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recentclinical results demonstrate that pegylated alpha-interferon is superiorto unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N.Engl. J. Med. 2000, 343, 1666-1672). However, even with experimentaltherapeutic regimens involving combinations of pegylatedalpha-interferon and ribavirin, a substantial fraction of patients donot have a sustained reduction in viral load. Thus, there is a clear andimportant need to develop effective therapeutics for treatment of HCVinfection.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I

where:

R¹ is CO₂R⁵ or CONR⁶R⁷; R² is

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, alkoxy, orhaloalkoxy;R⁴ is cycloalkyl;R⁵ is hydrogen or alkyl;R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)₂NSO₂,or) (R¹⁰)SO₂;R⁷ is hydrogen or alkyl;R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl,cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO₂,cycloalkylSO₂, haloalkylSO₂, aminocarbonyl, (alkylamino)carbonyl,(dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;R⁹ is hydrogen, alkyl, or cycloalkyl; andR¹⁰ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, or homomorpholinyl and is substitutedwith 0-3 alkyl substituents; or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a compound of formula I where

R¹ is CO₂R⁵ or CONR⁶R⁷; R² is a

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;R⁴ is cycloalkyl;R⁵ is hydrogen or alkyl;R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)₂NSO₂,or) (R¹⁰)SO₂;R⁷ is hydrogen or alkyl;R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl,alkoxycarbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;R⁹ is hydrogen or alkyl; andR¹⁰ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, orhomomorpholinyl;or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ isCONR⁶R⁷; R⁶ is alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)₂NSO₂, or(R¹⁰)SO₂; and R⁷ is hydrogen.

Another aspect of the invention is a compound of formula I where R³ ishydrogen.

Another aspect of the invention is a compound of formula I where R³ ismethoxy.

Another aspect of the invention is a compound of formula I where R⁴ iscyclohexyl.

Another aspect of the invention is a compound of formula I where R⁶ is(R⁹)₂NSO₂ or (R¹⁰)SO₂.

Another aspect of the invention is a compound of formula I where R⁶ is(dimethylamino)SO₂.

Another aspect of the invention is a compound of formula I where R⁶ isalkylSO₂.

Another aspect of the invention is a compound of formula I where R⁶ isisopropylSO₂.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Any scope of any variable, including R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,or R¹⁰, can be used independently with the scope of any other instanceof a variable.

Unless specified otherwise, these terms have the following meanings“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Cycloalkyl” means amonocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,”“alkoxy” and other terms with a substituted alkyl moiety includestraight and branched isomers composed of 1 to 6 carbon atoms for thealkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo substituted alkyl to perhalo substituted alkyl.“Aryl” includes carbocyclic and heterocyclic aromatic substituents.Parenthetic and multiparenthetic terms are intended to clarify bondingrelationships to those skilled in the art. For example, a term such as((R)alkyl) means an alkyl substituent further substituted with thesubstituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide,hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate,pamoate, phosphate, succinate, sulfate, tartrate, tosylate, andxinofoate. Some cationic salt forms include ammonium, aluminum,benzathine, bismuth, calcium, choline, diethylamine, diethanolamine,lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine,potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms(see, for example, the structures below). The invention includes allstereoisomeric forms, including enantiomers and diastereomers as well asmixtures of stereoisomers such as racemates. Some stereoisomers can bemade using methods known in the art. Stereoisomeric mixtures of thecompounds and related intermediates can be separated into individualisomers according to methods commonly known in the art. The use ofwedges or hashes in the depictions of molecular structures in thefollowing schemes and tables is intended only to indicate relativestereochemistry, and should not be interpreted as implying absolutestereochemical assignments.

Synthetic Methods

The compounds may be made by methods known in the art including thosedescribed below. Some reagents and intermediates are known in the art.Other reagents and intermediates can be made by methods known in the artusing readily available materials. The variables (e.g. numbered “R”substituents) used to describe the synthesis of the compounds areintended only to illustrate how to make and are not to be confused withvariables used in the claims or in other sections of the specification.Abbreviations used within the schemes generally follow conventions usedin the art.

Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate can be hydrolyzed to2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (See Scheme 1). Thiscompound can be condensed with a variety of sulfonyl ureas, using forexample, 1,1′-carbonyldiimidazole in combination with1,8-diazabicyclo[5.4.0]undec-7-ene in anhydrous THF. The resultant acylsulfamides can be subjected to known coupling reactions with a diversityof 2-formyl boronic acids or esters, using for example, Suzuki couplingconditions, to provide cyclic hemiaminal intermediates of the typedepicted. These compounds can be converted to indolobenzazepinesderivatives by treatment with methyl 2-(dimethoxyphosphoryl)acrylateunder the influence of cesium carbonate in DMF via consecutive Michaeland Horner Emmons reactions.

Related fused cyclopropyl ester derivatives can be generated by methodsknown in the art, including treatment of the indolobenzazepine esterswith trimethyl sulfoxonium iodide under strongly basic conditions inDMSO. The residual aliphatic ester moiety in the resultant fusedcyclopropanes can be hydrolyzed and the product acids can be condensedwith a variety of alkyl-bridged piperazines. For example,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateand diisopropyl ethyl amine in DMSO can give alkyl bridged piperazinecarboxamides.

N-protected piperazines can also be coupled to the intermediateindolobenzazepine acids and the resultant piperazine carboxamides can bedeprotected using methods known in the art and derivatized using avariety of synthetic protocols, some illustrative examples of which areshown below (See Scheme 2).

An intermediate useful for the synthesis of some compounds of theinvention involves the preparation of the tert-butyl esterindolobenzazepine shown in Scheme 3.

This methodology involves base catalyzed hydrolysis of the indole methylester shown, followed by its reaction with either thionyl chloride andpotassium tertiary butoxide, or alkylation with silver carbonate andtertiary butyl bromides. The resultant compound can be transformed usingchemistry analogous to that outlined previously to provide the mixedester indolobenzazepines shown above.

These intermediates are useful in an alternative procedure that can beemployed for the preparation of acylsulfamide and acylsulfonamidealkyl-bridged piperazines, as shown in Scheme 4. Cyclopropanation of anintermediate t-butyl ester indolobenzazepine and subsequent cleavage ofthe t-butyl ester group can generate the acid which can be coupled to adiversity of sulfonamides and sulfonylureas. Subsequent hydrolysisaffords the related aliphatic acid, which can be coupled with adiversity of alkyl-bridged piperazines. For example,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateand diisopropyl ethyl amine in DMSO can give the alkyl bridgedpiperazine carboxamides.

Some examples exist as stereoisomeric mixtures. The inventionencompasses all stereoisomers of the compounds. Methods of fractionatingstereoisomeric mixtures are well known in the art, and include but arenot limited to; preparative chiral supercritical fluid chromatography(SFC) and chiral high performance liquid chromatography (HPLC). Anexample using this approach is shown in scheme 5.

An additional method to achieve such separations involves thepreparation of mixtures of diastereomers which can be separated using avariety of methods known in the art. One example of this approach isshown below (Scheme 6).

Some diastereomeric amides can be separated using reverse phase HPLC.After hydroysis, the resultant optically active acids can be coupledwith bridged piperazine derivatives (Scheme 6). For example,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateand diisopropyl ethyl amine in DMSO can be used to give the alkylbridged piperazine carboxamides. Other standard acid amine couplingmethods can also be used to give optically active carboxamides.

Schemes 7-9 illustrate other methods of making intermediates andcompounds.

Biological Methods

The compounds demonstrated activity against HCV NS5B as determined inthe following HCV RdRp assays.

HCV NS5B RdRp Cloning, Expression, and Purification.

The cDNA encoding the NS5B protein of HCV, genotype 1b, was cloned intothe pET21a expression vector. The protein was expressed with an 18 aminoacid C-terminal truncation to enhance the solubility. The E. colicompetent cell line BL21(DE3) was used for expression of the protein.Cultures were grown at 37° C. for ˜4 hours until the cultures reached anoptical density of 2.0 at 600 nm. The cultures were cooled to 20° C. andinduced with 1 mM IPTG. Fresh ampicillin was added to a finalconcentration of 50 μg/ml and the cells were grown overnight at 20° C.

Cell pellets (3 L) were lysed for purification to yield 15-24 mgs ofpurified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500mM NaCl, 0.5% triton X-100, 1 mM DTT, 1 mM EDTA, 20% glycerol, 0.5 mg/mllysozyme, 10 mM MgCl₂, 15 ug/ml deoxyribonuclease I, and Complete TMprotease inhibitor tablets (Roche). After addition of the lysis buffer,frozen cell pellets were resuspended using a tissue homogenizer. Toreduce the viscosity of the sample, aliquots of the lysate weresonicated on ice using a microtip attached to a Branson sonicator. Thesonicated lysate was centrifuged at 100,000×g for 1 hr at 4° C. andfiltered through a 0.2 μm filter unit (Corning).

The protein was purified using two sequential chromatography steps:Heparin sepharose CL-6B and polyU sepharose 4B (Pharmacia). Thechromatography buffers were identical to the lysis buffer but containedno lysozyme, deoxyribonuclease I, MgCl2 or protease inhibitor and theNaCl concentration of the buffer was adjusted according to therequirements for charging the protein onto the column. Each column waseluted with a NaCl gradient which varied in length from 5-50 columnvolumes depending on the column type. After the final chromatographystep, the resulting purity of the enzyme is >90% based on SDS-PAGEanalysis. The enzyme was aliquoted and stored at −80° C.

Standard HCV NS5B RdRp Enzyme Assay.

HCV RdRp genotype 1b assays were run in a final volume of 60 μl in 96well plates (Corning 3600). The assay buffer is composed of 20 mM Hepes,pH 7.5, 2.5 mM KCl, 2.5 mM MgCl₂, 1 mM DTT, 1.6 U RNAse inhibitor(Promega N2515), 0.01 mg/ml BSA (Sigma B6917), and 2% glycerol. Allcompounds were serially diluted (3-fold) in DMSO and diluted further inwater such that the final concentration of DMSO in the assay was 2%. HCVRdRp genotype 1b enzyme was used at a final concentration of 28 nM. ApolyA template was used at 6 nM, and a biotinylated oligo-dT12 primerwas used at 180 nM final concentration. Template was obtainedcommercially (Amersham 27-4110). Biotinylated primer was prepared bySigma Genosys. 3H-UTP was used at 0.6 μCi (0.29 μM total UTP). Reactionswere initiated by the addition of enzyme, incubated at 30° C. for 60min, and stopped by adding 25 μl of 50 mM EDTA containing SPA beads (4μg/μl, Amersham RPNQ 0007). Plates were read on a Packard Top Count NXTafter >1 hr incubation at room temperature.

Modified HCV NS5B RdRp Enzyme Assay.

A modified enzyme assay was performed essentially as described for thestandard enzyme assay except for the following: The biotinylated oligodT12 primer was precaptured on streptavidin-coated SPA beads by mixingprimer and beads in assay buffer and incubating at room temperature forone hour. Unbound primer was removed after centrifugation. Theprimer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 andused in the assay at final concentrations of 20 nM primer and 0.67 μg/μlbeads. Order of addition in the assay: enzyme (1.75 nM) was added todiluted compound followed by the addition of a mixture of template (0.36nM), 3H-UTP (0.6 μCi, 0.29 μM), and primer-bound beads, to initiate thereaction; concentrations given are final. Reactions were allowed toproceed for 4 hours at 30° C.

IC₅₀ values for compounds were determined using seven different [I].IC₅₀ values were calculated from the inhibition using the formulay=A+((B−A)/(1+((C/x)̂D))).

FRET Assay Preparation.

The HCV FRET screening assay was performed in 96-well cell cultureplates. The FRET peptide (Anaspec, Inc.) (Taliani et al., Anal. Biochem.1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end ofthe peptide and an acceptor, DABCYL, near the other end. Thefluorescence of the peptide is quenched by intermolecular resonanceenergy transfer (RET) between the donor and the acceptor, but as the NS3protease cleaves the peptide the products are released from RETquenching and the fluorescence of the donor becomes apparent. The assayreagent was made as follows: 5× cell Luciferase cell culture lysisreagent from Promega (#E153A) diluted to 1× with dH₂O, NaCl added to 150mM final, the FRET peptide diluted to 20 μM final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renillaluciferase reporter gene, were trypsinized and plated in a 96-well platewith titrated test compounds added in columns 3 through 12; columns 1and 2 contained a control compound (HCV control inhibitor), and thebottom row contained cells with DMSO only. The plates were then placedin a CO₂ incubator at 37° C.

Assays.

Subsequent to addition of the test compounds described above (FRET AssayPreparation), at various times the plate was removed and Alamar bluesolution (Trek Diagnostics, #00-100) was added to measure cellulartoxicity. After reading in a Cytoflour 4000 instrument (PE Biosystems),plates were rinsed with PBS and then used for FRET assay by the additionof 30 ul of the FRET peptide assay reagent described above (FRET AssayPreparation) per well. The plate was then placed into the Cytoflour 4000instrument which had been set to 340 excite/490 emission, automatic modefor up to 20 cycles and the plate read in a kinetic mode. Typically, thesignal to noise using an endpoint analysis after the reads was at leastthree-fold. Alternatively, after Alamar blue reading, plates were rinsedwith PBS, then used for luciferase assay using the Promega Dual-GloLuciferase Assay System or the Promega EnduRen Live Cell Substrateassay.

Compound analysis was performed by quantification of the relative HCVreplicon inhibition and the relative cytotoxicity values. To calculatecytoxicity values, the average Alamar Blue fluorescence signals from thecontrol wells were set as 100% non-toxic. The individual signals in eachof the compound test wells were then divided by the average controlsignal and multiplied by 100% to determine percent cytotoxicity. Tocalculate the HCV replicon inhibition values, an average backgroundvalue was obtained from the two wells containing the highest amount ofHCV control inhibitor at the end of the assay period. These numbers weresimilar to those obtained from naïve Huh-7 cells. The background numberswere then subtracted from the average signal obtained from the controlwells and this number was used as 100% activity. The individual signalsin each of the compound test wells were then divided by the averagedcontrol values after background subtraction and multiplied by 100% todetermine percent activity. EC₅₀ values were calculated as theconcentration which caused a 50% reduction in FRET or luciferaseactivity. The two numbers generated for the compound plate, percentcytoxicity and percent activity, were used to determine compounds ofinterest for further analysis.

Representative data for compounds are reported in Table 1.

TABLE 1 Structure IC₅₀ EC₅₀

C B

B B

B B

B B

C B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

A A

A

B B

A

B A

B B

B B

B B

B B

B B

B B

B B

B B

B B

A D

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B E

B B

B

B B

B B

B B

B B

B B

B B

B B

B B A > 0.5 μM; B 0.001 μM-0.5 μM; C < 0.02 μM but an exact value wasnot determined; D > 0.04 μM; but an exact value was not determined, D >0.11 μM; but an exact value was not determined,;

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful intreating HCV and HCV infection. Therefore, another aspect of theinvention is a composition comprising a compound, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising acompound having anti-HCV activity.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is an interferon. Another aspect of theinvention is where the interferon is selected from interferon alpha 2B,pegylated interferon alpha, consensus interferon, interferon alpha 2A,and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is a cyclosporin. Another aspect of theinvention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is selected from the group consisting ofinterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from HCV metalloprotease, HCV serine protease, HCVpolymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCVegress, HCV NS5A protein, IMPDH, and a nucleoside analog for thetreatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound,or a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the functionof the HCV replicon comprising contacting the HCV replicon with acompound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the functionof the HCV NS5B protein comprising contacting the HCV NS5B protein witha compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable saltthereof. In another embodiment the compound is effective to inhibit thefunction of the HCV replicon. In another embodiment the compound iseffective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable saltthereof, in conjunction with (prior to, after, or concurrently) anothercompound having anti-HCV activity.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin iscyclosporin A.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from the group consisting of HCV metalloprotease, HCVserine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and anucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of targetin the HCV life cycle other than the HCV NS5B protein.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of hepatitis and HCV infection.

“Patient” means a person infected with the HCV virus and suitable fortherapy as understood by practitioners in the field of hepatitis and HCVinfection.

“Treatment,” “therapy,” “regimen,” “HCV infection,” and related termsare used as understood by practitioners in the field of hepatitis andHCV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients. Atherapeutically effective amount is that which is needed to provide ameaningful patient benefit. Pharmaceutically acceptable carriers arethose conventionally known carriers having acceptable safety profiles.Compositions encompass all common solid and liquid forms includingcapsules, tablets, losenges, and powders as well as liquid suspensions,syrups, elixers, and solutions. Compositions are made using commonformulation techniques, and conventional excipients (such as binding andwetting agents) and vehicles (such as water and alcohols) are generallyused for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating hepatitis andHCV infection. In these combination methods, the compound will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regime, however, willbe determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods arelisted in Table 2.

TABLE 2 Type of Inhibitor or Brand Name Target Source Company Omega IFNIFN-ω Intarcia Therapeutics BILN-2061 serine protease BoehringerIngelheim inhibitor Pharma KG, Ingelheim, Germany Summetrel antiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA Roferon A IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys PEGylated IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and RibavirinPEGylated IFN- F. Hoffmann-La Roche α2a/ribavirin LTD, Basel,Switzerland CellCept HCV IgG F. Hoffmann-La Roche immunosuppressant LTD,Basel, Switzerland Wellferon lymphoblastoid IFN- GlaxoSmithKline plc,αn1 Uxbridge, UK Albuferon - α albumin IFN-α2b Human Genome SciencesInc., Rockville, MD Levovirin ribavirin ICN Pharmaceuticals, Costa Mesa,CA IDN-6556 caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CAIP-501 antifibrotic Indevus Pharmaceuticals Inc., Lexington, MAActimmune INF-γ InterMune Inc., Brisbane, CA Infergen A IFN alfacon-1InterMune Pharmaceuticals Inc., Brisbane, CA ISIS 14803 antisense ISISPharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NYJTK-003 RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Pegasys andCeplene PEGylated IFN-α2a/ Maxim Pharmaceuticals immune modulator Inc.,San Diego, CA Ceplene immune modulator Maxim Pharmaceuticals Inc., SanDiego, CA Civacir HCV IgG Nabi immunosuppressant BiopharmaceuticalsInc., Boca Raton, FL Intron A and Zadaxin IFN-α2b/α1-thymosin RegeneRxBiopharmiceuticals Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc, SanMateo, CA Levovirin IMPDH inhibitor Ribapharm Inc., Costa Mesa, CAViramidine Ribavirin Prodrug Ribapharm Inc., Costa Mesa, CA Heptazymeribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO Intron A IFN-α2bSchering-Plough Corporation, Kenilworth, NJ PEG-Intron PEGylated IFN-α2bSchering-Plough Corporation, Kenilworth, NJ Rebetron IFN-α2b/ribavirinSchering-Plough Corporation, Kenilworth, NJ Ribavirin ribavirinSchering-Plough Corporation, Kenilworth, NJ PEG-Intron/RibavirinPEGylated IFN- Schering-Plough α2b/ribavirin Corporation, Kenilworth, NJZadazim Immune modulator SciClone Pharmaceuticals Inc., San Mateo, CARebif IFN-β1a Serono, Geneva, Switzerland IFN-β and EMZ701 IFN-β andEMZ701 Transition Therapeutics Inc., Ontario, Canada Batabulin (T67)β-tubulin inhibitor Tularik Inc., South San Francisco, CA MerimepodibIMPDH inhibitor Vertex Pharmaceuticals (VX-497) Inc., Cambridge, MATelaprevir NS3 serine protease Vertex Pharmaceuticals (VX-950,LY-570310) inhibitor Inc., Cambridge, MA/ Eli Lilly and Co. Inc.,Indianapolis, IN Omniferon natural IFN-α Viragen Inc., Plantation, FLXTL-6865 (XTL-002) monoclonal antibody XTL Biopharmaceuticals Ltd.,Rehovot, Isreal HCV-796 NS5B Replicase Wyeth/Viropharma Inhibitor NM-283NS5B Replicase Idenix/Novartis Inhibitor GL-59728 NS5B Replicase GeneLabs/Novartis Inhibitor GL-60667 NS5B Replicase Gene Labs/NovartisInhibitor 2′C MeA NS5B Replicase Gilead Inhibitor PSI 6130 NS5BReplicase Roche Inhibitor R1626 NS5B Replicase Roche Inhibitor SCH503034 serine protease Schering Plough inhibitor NIM811 CyclophilinInhibitor Novartis Suvus Methylene blue Bioenvision Multiferon Longlasting IFN Viragen/Valentis Actilon (CPG10101) TLR9 agonist ColeyInterferon-β Interferon-β-1a Serono Zadaxin Immunomodulator SciclonePyrazolopyrimidine HCV Inhibitors Arrow Therapeutics Ltd. compounds andsalts From WO- 2005047288 26 May 2005 2′C Methyl adenosine NS5BReplicase Merck Inhibitor GS-9132 (ACH-806) HCV InhibitorAchillion/Gilead

DESCRIPTION OF SPECIFIC EMBODIMENTS

Unless otherwise specified, analytical LCMS data on the followingintermediates and examples were acquired using the following columns andconditions. Stop time: Gradient time+1 minute; Starting conc: 0% Bunless otherwise noted; Eluent A: 5% CH₃CN/95% H₂O with 10 mM NH₄OAc(for columns A, D and E); 10% MeOH/90% H₂O with 0.1% TFA (for columns Band C); Eluent B: 95% CH₃CN/5% H₂O with 10 mM NH₄OAc (for columns A, Dand E); 90% MeOH/10% H₂O with 0.1% TFA (for columns B and C); Column A:Phenomenex 10μ 4.6×50 mm C18; Column B: Phenomenex C18 10μ 3.0×50 mm;Column C: Phenomenex 4.6×50 mm C18 10μ; Column D: Phenomenex Lina C18 5μ3.0×50 mm; Column E: Phenomenex 5μ 4.6×50 mm C18.

As an artifact of the graphics software, some structures have missinghydrogen atoms.

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester

Freshly recrystallized pyridinium tribromide (recrystallization from hotAcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuumover KOH) was added in portions (over 10 min.) to a stirring solution ofmethyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (preparedusing procedures describe in WO2004/065367) in CHCl₃/THF (1:1, 1.25 L)at 2° C. The reaction solution was stirred at 0-5° C. for 2.5 h, andwashed with sat. aq. NaHSO₃ (1 L), 1 N HCl (1 L) and brine (1 L). Theorganic layer was dried (MgSO₄) and concentrated. The resulting red oilwas diluted with Et₂O and concentrated. The resulting pink solid wasdissolved into Et₂O (200 mL) treated with hexanes (300 mL) and partiallyconcentrated. The solids were collected by filtration and rinsed withhexanes. The mother liquor was concentrated to dryness and the procedurerepeated. The solids were combined to yield 1H-indole-6-carboxylic acid,2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffypink solid, which was used without further purification. 1HNMR (300 MHz,CDCl₃) δ 8.47 (br s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.74 (dd, J=1.4, 8.8Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J=3.7, 11.7 Hz,1H), 1.98-1.72 (m, 7H), 1.50-1.27 (m, 3H). 13CNMR (75 MHz, CDCl₃) δ168.2, 135.6, 130.2, 123.1, 120.8, 120.3, 118.7, 112.8, 110.7, 52.1,37.0, 32.2 (2), 27.0 (2), 26.1. LCMS: m/e 334 (M−H)⁻, ret time 3.34 min,column A, 4 minute gradient.

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-

A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (20 g,60 mmol) and LiOH (3.8 g, 160 mmol) in MeOH/THF/H₂O (1:1:1, 300 mL) washeated at 90° C. for 2 h. The reaction mixture was cooled in an ice/H₂Obath, neutralized with 1M HCl (˜160 mL) diluted with H₂O (250 mL) andstirred for 1 h at rt. The precipitates were collected by filtrationrinse with H₂O and dried to yield 1H-indole-6-carboxylic acid,2-bromo-3-cyclohexyl-(quant.) which was used without furtherpurification.

An alternative procedure that can by used to provide1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl—is described below:

A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (117g, 349 mmol) and LiOH.H₂O (26.4 g, 629 mmol) in MeOH/THF/H₂O (1:1:1, 1.8L) was heated at reflux for 3 h. The reaction mixture was cooled in anice/H₂O bath to 2° C., neutralized with 1M HCl (˜650 mL) (added at sucha rate that temperature did not exceed 5° C.), diluted with H2O (1 L)and stirred while warming to ambient temperature. The precipitates werecollected by filtration rinsed with H₂O and dried to yield the mono THFsolvate of 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl- (135.5 g,345 mmol, 99%) as a yellow solid, which was used without furtherpurification. 1HNMR (300 MHz, CDCl₃) δ 11.01 (br s, 1H), 8.77 (s, 1H),8.07 (d, J=1.5 Hz, 1H), 7.82 (dd, J=1.5, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz,1H), 3.84-3.74 (m, 4H), 2.89 (m, 1H), 1.98-1.72 (m, 11H), 1.50-1.24 (m,3H). 13CNMR (75 MHz, CDCl₃) δ 172.7, 135.5, 130.7, 122.3, 120.9 (2),118.8, 113.3, 111.1, 67.9 (2), 37.0, 32.2 (2), 27.0 (2), 26.1, 25.5 (2).LCMS: m/e 320 (M−H)⁻, ret time 2.21 min, column A, 4 minute gradient.

1H-Indole-6-carboxamide,2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-

1,1′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirredsolution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g,6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO₂ was instantaneousand when it slowed the solution was heated at 50° C. for 1 hr and thencooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was addedfollowed by the dropwise addition of a solution of DBU (1.34 g, 8.8mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture waspartitioned between ethyl acetate and dilute HCl. The ethyl acetatelayer was washed with water followed by brine and dried over Na₂SO₄. Theextract was concentrated to dryness to leave the title product as a paleyellow friable foam, (2.0 g, 74%, >90% purity, estimated from NMR). ¹HNMR (300 MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H)2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d,J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).

An alternative method for the preparation of 1H-indole-6-carboxamide,2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]—is described below.

To a 1 L four necked round bottom flask equipped with a mechanicalstirrer, a temperature controller, a N2 inlet, and a condenser, underN2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g,0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g,0.31 mol) was added portion wise. The reaction mixture was then heatedto 50° C. for 2 h. After cooling to 30° C., N,N-dimethylaminosulfonamide(41.7 g, 0.336 mol) was added in one portion followed by addition of DBU(54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reactionmixture was then stirred at rt for 20 h. The solvent was removed invacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2L). The organic layer was separated and the aqueous layer was extractedwith EtOAc (500 mL). The combined organic layers were washed with brine(1.5 L) and dried over MgSO₄. The solution was filtered and concentratedin vacuo to give the crude product (111.0 g). The crude product wassuspended in EtOAc (400 mL) at 60° C. To the suspension was addedheptane (2 L) slowly. The resulting suspension was stirred and cooled to0° C. It was then filtered. The filter cake was rinsed with small amountof heptane and house vacuum air dried for 2 days. The product wascollected as a white solid (92.0 g, 83%). ¹H NMR (MeOD, 300 MHz) δ 7.89(s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01(s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z429 (M+H)+.

1H-Indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-

A mixture of the2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide(4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015mol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (41 mg, 0.0001mol), palladium acetate (11.2 mg), and finely ground potassium carbonate(4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and undernitrogen for 30 min, at which time LC/MS analysis showed the reaction tobe complete. The reaction mixture was then diluted with ethyl acetateand water, and then acidified with an excess of dilute HCl. The ethylacetate layer was then collected and washed with dilute HCl, water andbrine. The organic solution was then dried (magnesium sulfate), filteredand concentrated to give a gum. The gum was diluted with hexanes (250ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at22° C. during which time the product was transformed into a brightyellow granular solid (4.8 g) which was used directly without furtherpurification.

An alternative procedure for the preparation of 1H-indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)—isprovided below:

To a slurried solution of2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide(54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added asolution of Na₂CO₃ (40.1 g, 379 mmol) in water (380 mL). The reactionmixture was stirred 10 min. and then Pd(PPh₃)₄ (11.3 g, 10.0 mmol) wasadded. The reaction solution was flushed with nitrogen and heated at 70°C. (internal monitoring) overnight and then cooled to rt. The reactionwas diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1Naqueous HCl (1 L) and brine (500 mL), dried (MgSO₄), filtered andconcentrated. The residual solids were stirred with Et2O (600 mL) for 1h and collected by filtration to yield 1H-indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-(52.8 g, 109 mmol, 87%) as a yellow powder which was used withoutfurther purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s,1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4,8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d,J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74(m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl₃) δ 165.7, 158.8,147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3,110.4, 109.8, 79.6, 45.9, 37.2 (2), 34.7, 32.0 (2), 25.9 (2), 24.9.LCMS: m/e 482 (M−H)⁻, ret time 2.56 min, column A, 4 minute gradient.

6H-Isoindolo[2,1-a]indole-3-carboxamide,11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-

To a 5 L four necked round bottom flask equipped with a temperaturecontroller, a condenser, a N2 inlet and a mechanical stirrer, wascharged toluene (900 mL), EtOH (900 mL),2-bromo-3-cyclohexyl-N—(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide(90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbledwith N₂ for 15 mins. A solution of Na₂CO₃ (66.8 g, 0.63 mol) in H₂O (675mL) was added and the reaction mixture was bubbled with N₂ for another(10 mins). Pd(PPh₃)₄ (7.0 g, 6.3 mmol) was added and the reactionmixture was heated to 70° C. for 20 h. After cooling to 35° C., asolution of 1 N HCl (1.5 L) was added slowly. The resulting mixture wastransferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5L). The combined organic extracts were washed with brine (2 L), driedover MgSO₄, filtered and concentrated in vacuo to give a yellow solid,which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.)to give3-cyclohexyl-N—(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.

The mother liquid from the trituration was concentrated in vacuo. Theresidue was refluxed with EtOH (50 mL) for 3 h. The solution was thencooled to 0° C. The precipitates were filtered and washed with cooledTBME (5° C.) (20 mL). The filter cake was house vacuum air dried to givea further quantity of the title compound as a white solid (16.0 g). HPLCpurity, 99%. ¹H NMR (CDCl₃, 300 MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73(d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4 and 1.4 Hz,1H), 7.09 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.4 and 2.2 Hz, 1H), 6.50 (s,1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7H),1.40-1.42 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). m/z 512 (M+H)⁺.

1H-indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-

11-cyclohexyl-N—(N,N-dimethylsulfamoyl)-6-ethoxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamidewas dissolved in THF (75 mL). To the solution was added a solution of 2N HCl (300 mL). The mixture was vigorously stirred under N2 at rt for 16h. The resulting suspension was filtered and washed with cooled TBME(2×30 mL). the filer cake was vacuum air dried overnight to give thetitle compound as a yellow solid. HPLC purity, 99% ¹H NMR (DMSO-d6, 300MHz) δ 11.65 (s, 1H), 8.16 (s, 1H), 7.76 (d, J=5.9 Hz, 1H), 7.73 (d,J=5.9 Hz, 1H), 7.58 (dd, J=8.5 and 1.5 Hz, 1H), 7.17-7.20 (m, 2H), 7.08(dd, J=8.5 and 1.4 Hz, 1H), 6.55 (d, J=8.6 Hz, 1H), 3.86 (s, 3H),3.14-3.18 (m, 1H), 2.91 (s, 6H), 1.75-1.99 (m, 7H), 1.48-1.60 (m, 3H);m/z 484 (M+H)+.

7H-Indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-,methyl ester

A mixture of the3-cyclohexyl-N—(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(4.8 g, 0.01 mol), methyl 2-(dimethoxyphosphoryl)acrylate (9.7 g, 0.02mol) and cesium carbonate (7.1 g, 0.02 mol) in DMF (28 mL) was stirredfor 20 hr at an oil bath temperature of 55° C. The mixture was pouredinto icewater and acidified with dilute HCl to precipitate the crudeproduct. The solid was collected, dried and flash chromatographed onSiO₂ (110 g) using an ethyl acetate and methylene chloride (1:10)solution containing 2% acetic acid. Homogeneous fractions were combinedand evaporated to afford the title compound as a pale yellow solid (3.9g, 71% yield). MS: 552 (M=H+).

An alternate procedure for the preparation of7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-,methyl ester is provided below.

A solution of11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide(cyclic hemiaminal) (63.0 g, 130 mmol), methyl2-(dimethoxyphosphoryl)acrylate (60 g, 261 mmol), cesium carbonate (106g, 326 mmol) in DMF (400 mL) was heated at 60° C. (bath temp) for 4.5 h.Additional methyl 2-(dimethoxyphosphoryl)acrylate (15 g, 65 mmol) andcesium carbonate (21.2 g, 65 mmol) were added and the reaction washeated at 60° C. overnight then and cooled to rt. The stirring reactionmixture was diluted with H₂O (1 L), slowly neutralized with 1N aqueousHCl (800 mL), stirred 3 h, and then the precipitates were collected byfiltration. The solids were triturated with Et2O (800 mL) and dried toyield methyl 7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-,methyl ester (70.2 g, 127 mmol, 98%) as a yellow solid which was usedwithout further purification. 1HNMR (300 MHz, CDCl₃) δ 8.67 (s, 1H),8.09 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J=8.4 Hz,1H), 7.42 (d, J=8.8 Hz, 1H), 7.08 (dd, J=2.6, 8.8 Hz, 1H), 6.98 (d,J=2.6 Hz, 1H), 5.75-5.51 (m, 1H), 4.29-4.01 (m, 1H), 3.89 (s, 3H), 3.82(s, 3H), 3.05 (s, 6H), 2.87-2.73 (m, 1H), 2.11-1.12 (m, 10H). LCMS: m/e550 (M−H)−, ret time 3.21 min, column A, 4 minute gradient.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (+/−)-

DMSO (5 mL) was added to a mixture of trimethylsulfoxonium iodide (199mg, 0.906 mmol) and NaH (38 mg in 60% oil dispersion, 0.953 mmol) in around-bottomed flask. The reaction mixture was stirred at rt for 0.5 hr.7H-Indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-(methoxy)-,methyl ester (125 mg, 0.227 mmol) was then added and the reactionmixture was stirred at rt. for 3 hr., and then at 50° C. for a further 3hr. The reaction was then quenched with water and acidified with 1N HClsolution. The crude product then precipitated as a light yellow solidwhich was collected by filtration and air dried, (106 mg, 83% yield). 6mg of this material was then purified by Prep. HPLC to afford the titlecompound as a light yellow solid (1.8 mg). MS m/z 566 (MH⁺), Retentiontime: 3.850 min. 1H NMR (500 MHz, MeOD) δ ppm 0.28 (m, 0.36H) 1.19-2.20(m, 11.64H) 2.70-3.02 (m, 2H) 3.03 (s, 2.16H) 3.05 (s, 3.84H) 3.49 (d,J=15.26 Hz, 0.64H) 3.54 (s, 1.92H) 3.83 (s, 1.08H) 3.91 (s, 3H) 4.08 (d,J=15.26 Hz, 0.36H) 5.29 (d, J=15.26 Hz, 0.36H) 5.50 (d, J=14.95 Hz,0.64H) 6.98-7.06 (m, 1H) 7.16 (d, J=2.44 Hz, 0.36H) 7.23 (d, J=2.44 Hz,0.64H) 7.30 (d, J=8.55 Hz, 0.64H) 7.34 (d, J=8.55 Hz, 0.36H) 7.56 (dd,J=8.55, 1.53 Hz, 0.64H) 7.63 (dd, J=8.55, 1.53 Hz, 0.36H) 7.88 (d,J=8.55 Hz, 0.64H) 7.91 (d, J=8.55 Hz, 0.36H) 8.12 (s, 0.36H) 8.33 (d,J=1.53 Hz, 0.64H).

An alternative procedure for the preparation of the title compounds isprovided below.

To a flame dried, four necked, 1 L round bottom flask equipped with amechanical stirrer, N2 inlet and a thermometer, under N2, was chargedsodium hydride (95%) (3.09 g, 129.2 mmol) and dry DMF (200 mL). Withvigorous stirring, trimethylsulfoxonium iodide (32.5 g, 147.3 mmol)portion wise during which time the temperature rose to 30° C. Afterstirring for 30 mins, a solution of7H-Indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-(methoxy)-,methyl ester (33.8 g, 61.3 mmol) in dry DMF (70 mL) was added quickly.The reaction mixture was stirred below 30° C. for 30 mins and thenpoured into an ice cold solution of 1 N HCl (130 mL) in H2O (2 L)portion wise. After the resulting suspension was mechanically stirredfor 1 h, the precipitates were filtered and the filter cake was washedwith H2O (100 mL). The filter cake was partitioned between EtOAc and 0.5N HCl (1:1, 4 L). The organic phase was separated, washed with H2O (1 L)and brine (1 L), dried over MgSO₄, filtered and concentrated in vacuo.The residue was dissolved in EtOAc (150 mL), and the solution wasfiltered through a silica gel pad (300 g in hexane) and rinsed with 50%EtOAc in hexane (5 L). The filtrate was concentrated in vacuo to give aslightly yellow solid which was triturated with 10%

EtOAc in TBME (220 mL) from 50° C. to 0° C. to givecycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (+/−)- as a white solid (26.1 g, 75% yield). HPLC purity,100%. ¹H NMR (DMSO-d₆, 300 MHz) δ 11.61 (s, 1H), 8.47 (s, 0.5H), 8.25(s, 0.5H), 7.81-7.88 (m, 1H), 7.57-7.63 (m, 1H), 7.23-7.29 (m, 2H),7.01-7.07 (m, 1H), 5.43 (d, J=15.0 Hz, 0.5H), 5.22 (d, J=15 Hz, 0.5H),4.04 (dd, J=15.4 and 6.6 Hz, 0.5H), 3.83 (s, 3H), 3.75 (s, 1H),3.08-3.47 (m, 0.5H), 3.29 (s, 3H), 2.73-2.92 (m, 8H), 1.11-1.99 (m,10.5H), 0.20 (m, 0.5H); m/z 566 (M+H)⁺.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (−)-

A sample of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-methyl ester was dissolved in EtOH/CH₃CN 1/1+0.5% DEA at a concentrationof 50 mg/ml. [The addition of DEA ensures the compound remains insolution during the injection process]. This solution was then injectedonto a Thar SFC-350 preparative SFC under the conditions shown below.

Preparative Conditions on Thar SFC-350:

Column: Chiralcel OJ-H 5×25 cm; mobile phase: 25% MeOH/CH₃CN (1/1) inCO₂; pressure (bar): 100; flow rate (ml/min): 240; solutionconcentration (mg/ml): 50; injection amount (ml): 4.5-5; Cycle time(min/inj): 6.5-7; Temperature (° C.): 45; throughput (g/hr): 2; Detectorwavelength (nm): 254.

From 371.4 g of racemic starting material, a total of 177.3 g of thedesired second eluting (−) isomer was obtained, containing ˜1 Meq ofdiethylamine. This material was purified using the following procedure.The mixture (24.7 g) dissolved in dichloromethane (800 mL)) was washedsequentially with; 0.5 N HCl (1×400 mL, 1×240 mL), H₂O (2×240 mL), andbrine (2×240 mL). The organic layer was then dried (Anhy Na₂SO₄),filtered and evaporated to give 22.33 g of(cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (−)—as a yellow solid (92% recovery). HPLC¹>99% (Rt 2.38min); LC/MS (ES⁺) 566.51 (M+H, 100); [α]_(D) ^(25C)−194.64° (c 1.03,MeOH). Anal. Calcd for C₃₀H₃₅N₃O₆S.0.33H₂O: C, 63.04; H, 6.29; N, 7.35;S, 5.61; H₂O, 1.04. Found: C, 63.07; H, 6.01; N, 7.24; S, 5.58; H₂O,1.03. The NMR shows the absence of Et₂NH. The EE of this material wasdetermined to be >99% using the following analytical HPLC procedure.

Analytical Conditions of ee Determination on Thar Analytical SFC.

Analytical Column: Chiralcel OJ (0.46×25 cm, 10 μl); BPR pressure: 100bars; Temperature: 35° C.; Flow rate: 3.0 ml/min; Mobile Phase: 15%MeOH/CH₃CN (1/1) in CO₂; Detector Wavelength: 254 nm; Retention time(min): 4, 6.5.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(−)-

To a solution of (−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester (22.33 g, 39.5 mmol) in MeOH (300 mL) was added 1 N NaOH(120 mL) slowly over 20 min., while maintaining the reaction temperature<30° C. The mixture was stirred at rt under N₂ for 18 h. The HPLCindicated the reaction was complete. To the reaction solution was added1 N HCl (130 mL). After addition was complete, the pH of the reactionmixture was about 2. The methanol in the reaction mixture wasevaporated. Water (300 mL) was added to the mixture which was thenextracted with CH₂Cl₂ (1×600 mL, 1×200 mL). The combined extracts werewashed with H₂O (2×300 mL), brine (2×300 mL), dried (Na₂SO₄) andevaporated to give 20.82 g (96% yield) of the title compound as a yellowsolid. HPLC conditions column: Phenomenoex Synergi Polar-RP 4 um 4.6×50mm; UV: 220 nm; gradient time: 4 min; flow rate: 4 mL/min, 75-100% B;solvent A: 10% MeOH/90% H₂O with 0.2% H₃PO₄, solvent B: 90% MeOH/10% H₂Owith 0.2% H₃PO₄. HPLC >99% (Rt 1.80 min.) LC/MS (ES⁺) 552.25 (M+H, 100);[α]_(D) ^(25C)−166.99° (c 1.00, MeOH). GC analysis: CH₂Cl₂ 4.94%; Anal.Calcd for C₂₉H₃₃N₃O₆S.0.16 H₂O.0.35 CH₂Cl₂:C, 60.37; H, 5.87; N, 7.20;S, 5.49; H₂O, 0.49; CH₂Cl₂, 5.02. Found: C, 59.95; H, 5.89; N, 7.03; S,5.38; H₂O, 0.47; CH₂Cl₂, 4.94.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+/−)-

To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester (100 mg, 0.177 mmol) in THF/Methanol mixture (2.0 mL/2.0mL), 2N NaOH solution (1.0 mL) was added. The reaction mixture washeated at 90° C. under microwave conditions for 5 min. It was thenconcentrated, acidified with 1N HCl solution and extracted with ethylacetate (2×20 mL). The organic layers were combined, dried (MgSO₄),filtered and concentrated. The residue was purified by preparative HPLCto afford the desired product as a light yellow solid, (59 mg, 60%yield). MS m/z 552 (MH⁺), Retention time: 3.850 min. 1H NMR (300 MHz,MeOD) δ ppm 0.25 (m, 0.38H) 1.14-2.22 (m, 11.62H) 2.69-2.98 (m, 2H) 3.02(s, 2.28H) 3.02 (s, 3.72H) 3.41 (d, J=15.00 Hz, 0.62H) 3.88 (s, 3H) 4.01(d, J=15.00 Hz, 0.38H) 5.26 (d, J=15.00 Hz, 0.38H) 5.45 (d, J=14.64 Hz,0.62H) 6.94-7.02 (m, 1H) 7.13 (d, J=2.56 Hz, 0.38H) 7.21 (d, J=2.20 Hz,0.62H) 7.26 (d, J=8.42 Hz, 0.62H) 7.30 (d, J=8.78 Hz, 0.38H) 7.53 (dd,J=8.42, 1.46 Hz, 0.62H) 7.61 (dd, J=8.60, 1.65 Hz, 0.38H) 7.85 (d,J=8.42 Hz, 0.62H) 7.89 (d, J=8.42 Hz, 0.38H) 8.10 (s, 0.38H) 8.28 (d,J=1.46 Hz, 0.62H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]-

TBTU (437 mg, 1.36 mmol) and DIPEA (0.95 mL, 5.436 mmol) were added to asolution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(500mg, 0.906 mmol) in DMSO (20.0 mL). The reaction mixture was stirred atrt for 15 min. (2S,3R)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol(280 mg, 1.36 mmol) was then added and the reaction mixture was stirredat rt overnight. The reaction mixture was quenched with water andacidified with 1N HCl solution. A brown solid separated which wascollected by filtration. This material was then fractionated byPreparative HPLC under the following conditions. Column: Waters Sunfire19 mm×100 mm; Solvent A: 10% CH3CN-90% H2O-0.1% TFA; Solvent B: 90%CH₃CN-10% H2O-0.1% TFA; Program: Start with 65% solvent B, initial holdtime for 5 min, then gradually increase to 90% solvent B in 30 min withflow rate 25 mL/min. Load: 50-60 mg/run.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]- elutes beforeCycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N″-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]- under the HPLC conditions described above. Productobtained as a light yellow solid, 230 mg, 36% yield). MS m/703 (MH),Retention time: 3.936 min. 1H NMR (500 MHz, MeOD) δ ppm 0.14-0.24 (m,2.64H) 0.51 (s, 2.46H) 0.72-2.21 (m, 20.9H) 2.49 (m, 0.18H) 2.62 (m,0.82H) 2.85 (m, 0.18H) 2.96 (m, 0.82H) 3.03 (s, 6H) 3.39 (m, 0.82H)3.49-3.58 (m, 1.64H) 3.71-3.80 (m, 0.36H) 3.90 (s, 3H) 4.17 (d, J=14.65Hz, 0.18H) 5.06 (d, J=14.65 Hz, 0.18H) 5.37 (d, J=14.95 Hz, 0.82H) 6.73(d, J=5.49 Hz, 0.82H) 6.98-7.05 (m, 1H) 7.08 (d, J=4.58 Hz, 0.18H) 7.10(d, J=2.44 Hz, 0.18H) 7.21 (d, J=2.44 Hz, 0.82H) 7.31 (d, J=8.55 Hz,0.82H) 7.34 (d, J=8.55 Hz, 0.18H) 7.59-7.64 (m, 1H) 7.87-7.93 (m, 1H)7.99 (s, 0.18H) 8.09 (d, J=1.22 Hz, 0.82H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]-

TBTU (437 mg, 1.36 mmol) and DIPEA (0.95 mL, 5.436 mmol) were added to asolution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(500mg, 0.906 mmol) in DMSO (20.0 mL). The reaction mixture was stirred atrt for 15 min. Then(2S,3R)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (280 mg, 1.36mmol) was added, and the reaction mixture was stirred at rt overnight.The reaction mixture was quenched with water and then acidified with 1NHCl solution. A brown colored solid separated that was collected byfiltration. This material was then fractionated by preparative HPLCunder the following conditions. Column: Waters Sunfire 19 mm×100 mm;Solvent A: 10% CH₃CN-90% H₂O-0.1% TFA; Solvent B: 90% CH₃CN-10% H₂O-0.1%TFA; Program: Start with 65% solvent B, initial hold time for 5 min,then gradually increase to 90% solvent B in 30 min with flow rate 25mL/min. Load: 50-60 mg/run.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]-elutes aftercycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]- under the HPLC conditions described above. Productobtained as a light yellow solid, 215 mg, 34% yield). MS m/703 (MH),Retention time: 4.038 min. 1H NMR (500 MHz, MeOD) δ ppm 0.20 (m, 0.38H)0.75 (s, 1.86H) 0.76 (s, 1.86H) 0.84 (s, 1.86H) 0.85 (s, 1.14H)0.89-2.18 (m, 18.9H) 2.52 (m, 0.38H) 2.70 (m, 0.62H) 2.85 (m, 0.38H)2.97 (m, 0.62H) 3.03 (s, 2.28H) 3.04 (s, 3.72H) 3.33-3.39 (m, 0.62H)3.43-3.51 (m, 1.24H) 3.73-3.77 (m, 0.38H) 3.78-3.84 (m, 0.38H) 3.90 (s,1.86H) 3.90 (s, 1.14H) 4.14 (d, J=14.65 Hz, 0.38H) 5.11 (d, J=14.65 Hz,0.38H) 5.44 (d, J=15.26 Hz, 0.62H) 6.68 (d, J=4.88 Hz, 0.62H) 6.96-7.03(m, 1H) 7.07 (d, J=5.19 Hz, 0.38H) 7.12 (d, J=2.44 Hz, 0.38H) 7.23 (d,J=2.14 Hz, 0.62H) 7.27 (d, J=8.54 Hz, 0.62H) 7.33 (d, J=8.54 Hz, 0.38H)7.55 (dd, J=8.39, 1.68 Hz, 0.62H) 7.62 (dd, J=8.55, 1.53 Hz, 0.38H) 7.87(d, J=8.54 Hz, 0.62H) 7.91 (d, J=8.55 Hz, 0.38H) 8.08 (d, J=1.22 Hz,0.38H) 8.10 (d, J=1.22 Hz, 0.62H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(−)-

10 N NaOH (2.0 mL, 20 mmol) solution and 4 mL of water were added to asolution ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]-(160 mg, 0.228 mmol) in THF/MeOH (7 mL/7 mL). Thereaction mixture was heated at 120° C. under microwave conditions for 1hr. It was then concentrated, acidified with conc. HCl solution andextracted with ethyl acetate twice (2×30 mL). The organic layers werecombined, dried (MgSO₄), filtered and concentrated in vacuo to an orangeoil. The crude product was then purified by Prep. HPLC column to affordthe product a light yellow solid, (80 mg, 64% yield). Average specificrotation −130.85°; Solvent MeOH; Wavelength 589 nm; 50 cm cell. MS m/552(MH⁺), Retention time: 3.760 min. 1H NMR (500 MHz, MeOD) δ ppm 0.27 (m,0.38H) 1.14-2.22 (m, 11.62H) 2.76 (m, 0.38H) 2.80-2.92 (m, 1H) 2.92-3.09(m, 6.62H) 3.45 (d, J=14.95 Hz, 0.62H) 3.90 (s, 1.86H) 3.91 (s, 1.14H)4.04 (d, J=15.26 Hz, 0.38H) 5.28 (d, J=15.26 Hz, 0.38H) 5.47 (d, J=15.26Hz, 0.62H) 6.95-7.05 (m, 1H) 7.15 (d, J=2.75 Hz, 0.38H) 7.23 (d, J=1.83Hz, 0.62H) 7.28 (d, J=8.55 Hz, 0.62H) 7.33 (d, J=8.54 Hz, 0.38H) 7.54(dd, J=8.39, 1.68 Hz, 0.62H) 7.63 (dd, J=8.55, 1.53 Hz, 0.38H) 7.86 (d,J=8.55 Hz, 0.62H) 7.91 (d, J=8.55 Hz, 0.38H) 8.11 (d, J=1.22 Hz, 0.62H)8.29 (d, J=1.22 Hz, 0.38H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+)-

10 N NaOH (1.8 mL, 18 mmol) solution and 4 mL of water were added to asolution ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]-(130 mg, 0.185 mmol) in bTHF/MeOH (7 mL/7 mL). Thereaction mixture was heated at 120° C. under microwave conditions for 1hr. It was concentrated, acidified with conc. HCl solution and extractedwith ethyl acetate twice (2×30 mL). The organic layers were combined,dried (MgSO₄), filtered and concentrated in vacuo to give an orange oil.The crude product was then purified by Prep. HPLC column to afford theproduct as a light yellow solid, (68 mg, 67% yield). Average specificrotation +174.73°; Solvent MeOH; Wavelength 589 nm; 50 cm cell MS m/552(MH⁺), Retention time: 3.773 min. 1H NMR (500 MHz, MeOD) δ ppm 0.27 (m,0.38H) 1.14-2.22 (m, 11.62H) 2.76 (m, 0.38H) 2.80-2.92 (m, 1H) 2.92-3.09(m, 6.62H) 3.45 (d, J=14.95 Hz, 0.62H) 3.90 (s, 1.86H) 3.91 (s, 1.14H)4.04 (d, J=15.26 Hz, 0.38H) 5.28 (d, J=15.26 Hz, 0.38H) 5.47 (d, J=15.26Hz, 0.62H) 6.95-7.05 (m, 1H) 7.15 (d, J=2.75 Hz, 0.38H) 7.23 (d, J=1.83Hz, 0.62H) 7.28 (d, J=8.55 Hz, 0.62H) 7.33 (d, J=8.54 Hz, 0.38H) 7.54(dd, J=8.39, 1.68 Hz, 0.62H) 7.63 (dd, J=8.55, 1.53 Hz, 0.38H) 7.86 (d,J=8.55 Hz, 0.62H) 7.91 (d, J=8.55 Hz, 0.38H) 8.11 (d, J=1.22 Hz, 0.62H)8.29 (d, J=1.22 Hz, 0.38H).

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethylester

To a mechanically stirred solution of2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (80 g, 0.24 m) in drymethylene dichloride(1.2 L) and THF (100 mL) were added activatedmolecular sieves (4A, 80 g) and silver carbonate (275 g, 0.99 m). Thereaction mixture was cooled to 0° C. and t-Butyl bromide (142 g, 1.04 m)was added drop wise. The mixture was stirred overnight at rt andmonitored by TLC (Hexane-Ethyl acetate 80:20, R_(f) (Product)=0.7). Ifany bromo acid was left unconverted a further 10% of silver carbonatewas added and stirring was continued for an addition 2-4 h. Oncompletion, the reaction mixture was filtered through a thin bed ofcelite. The filtrand was washed with methylene dichloride (500 mL). Thecombined filtrates were concentrated in-vacuo, and the crude productthus obtained was purified by silica gel chromatography: (230-400 mesh,eluted with a gradient of ethyl acetate in pet ether 0-2%). Homogeneousfractions were combined and evaporated under reduced pressure to give 80g (85%) of the title compound. HPLC:90.1% (RT=6.56 min), Column:C18 BDS,(50×4.6 mm), Mobile Phase:Gradient of 0.1% TFA in water:ACN (30→100→30),Flow rate 0.8 mL/min. LCMS:99.8% (RT=4.44 min), Column:Geneis, C1850×4.6 mm Mobile Phase:Gradient of 0.1% Formic acid in water:ACN(70→95→70), Flow rate:0.8 mL/min; M 1=376.5; ¹H NMR CDCl₃) (400 MHz) δ1.37-1.40 (m, 3H, cyc.Hexyl), 1.62 (s, 9H, t-Bu), 1.80-1.94 (two sets ofm, 3H, & 4H respectively, cyc.Hexyl part), 2.81 (m, 1H, CH ofcyc.Hexyl-benzylic), 7.70-7.75 (m, 2H, Indole-H_(4&5)), 8.04 (s, 1H,Indole-H₇), 8.52 (s, 1H, Indole-NH).

1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-,1,1-dimethylethyl ester

tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m)was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) anddegasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodiumcarbonate (720 mL, 1.0 M solution degasified separately,) andPd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h,2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and thereaction mixture was heated to 85° C. for 4 h. The reaction was thenmonitored by TLC, (Hexane-Ethyl acetate 80:20, R_(f) (Product)=0.55). Oncompletion, the reaction mixture was cooled to rt and water (1.0 L) wasadded followed by ethyl acetate (1.0 L). The organic layer was washedwith brine, and dried and concentrated under vacuum to afford the titlecompound as a yellow solid. Yield 75 g (74%). HPLC:99.7% (RT=6.30 min),Column:C18 BDS (4.6×50 mm), SC-307, Mobile Phase:Gradient of 0.1% TFA inwater:ACN (30→100→30), Flow rate 0.8 mL/min. LCMS:98.0% (RT=5.28 min),Column:Geneis, C18 (50×4.6 mm), Mobile Phase:Gradient of 0.1% Formicacid in water:ACN (70→95→70), Flow rate:0.8 mL/min; M−1=432.2; ¹H NMR(DMSO d₆) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu),1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH ofcyc.Hexyl-benzylic), 3.84 (s, 3H, OCH₃), 6.55 (d, J=4 Hz, 1H, arylH_(2′)), 7.06 (d, 1H, aryl H_(3′)), 7.08 (s, 1H, aryl H_(6′)), 7.23 (d,1H, Indole-H₅), 7.53 (d, J=8 Hz, 1H, Indole-H₄), 7.70-7.75 (m, 2H,NH+Indole-H₇), 8.06 (s, 1H, CHO).

7H-Indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-,10-(1,1-dimethylethyl) 6-methyl ester

tert-Butyl3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxylate (62.5g, 0.144 m) was dissolved in dry DMF (1.2 L) and stirred mechanically.Cesium carbonate (84 g, 0.17 m) and methyl2-(dimethoxyphosphoryl)acrylate (65-70% GC pure, 56.2 g, 0.18 m) werethen added and the reaction mixture was heated to 65° C. for 4 h, andthe reaction was monitored by TLC (Hexane-Ethyl acetate 80:20, R_(f)(Product)=0.7). On completion, the mixture was cooled to rt, thenquenched with water (1.0 L). A yellow solid precipitated, which wascollected by filtration and air dried. This material was then slurriedin methanol, filtered, and dried under vacuum to give the product as ayellow powder, (70 g, 90%). HPLC:99.1% (RT=6.45 min), Column:C18 BDS(4.6×50 mm), Mobile Phase:Gradient of 0.1% TFA in water:ACN (30→100→30),Flow rate 0.8 mL/min. LCMS:100% (RT=7.00 min), Column:Geneis, C18(50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water:ACN(70→95→70), Flow rate:0.8 mL/min; M+1=502.2; ¹H NMR (CDCl₃) (400 MHz) δ1.10-1.30 (m, 3H, cyc.Hexyl), 1.64 (s, 9H, t-Bu), 1.77-2.07 (m, 7H,cyc.Hexyl part), 2.80 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H,OCH₃), 3.93 (s, 3H, COOCH₃), 4.15 & 5.65 (two br. peak., 1H each,allylic CH₂), 6.95 (s, 1H, aryl H_(6′)), 7.01 (d, 1H, aryl H_(2′)), 7.53(d, J=8 Hz, 1H, aryl H_(3′)), 7.70 (d, J=4 Hz, 1H, Indole-H₅), 7.84(s+d, 2H, olefinic H+Indole-H₄), 8.24 (s, 1H, indole H₇); ¹³C NMR(CDCl₃) (100.0 MHz) δ 166.92, 165.71, 158.96, 142.28, 136.47, 13.50,134.61, 132.43, 132.01, 129.73, 124.78, 124.68, 120.33, 119.39, 119.04,115.62, 115.05, 111.27, 80.27, 55.49, 52.50, 39.09, 36.81, 33.40, 28.38,27.15, 26.28.

2-Propenoic acid, 2-(dimethoxyphosphinyl)-, methyl ester

To a 5 L four necked round bottom flask equipped with a mechanicalstirrer, a condenser, a temperature controller and a N2 inlet, wascharged paraformaldehyde (40.5 g, 1.35 mol), MeOH (2 L) and piperidine(2 mL). The reaction mixture was heated to reflux under N2 for 3 h.After cooling to 50° C., 2-(dimethoxyphosphoryl)acetate (150 g, 0.824mol) was added in one portion. The reaction mixture was continued toreflux for 18 h. After cooling to rt, the reaction solution wasconcentrated in vacuo to give a clear colorless oil. The above oil wasdissolved in dry toluene (1 L) in a 3 L four necked round bottom flaskequipped a temperature controller, a N₂ inlet, a magnetic stirrer and aDean-Stark apparatus. To the solution was added TsOH.H₂O (5.2 g). Thereaction mixture was then refluxed azeotropically to remove methanol for18 h. After cooling to rt, the solution was concentrated in vacuo togive a yellow oil which was vacuum distilled at 150-155° C./0.2 mmHg toafford the product as a colorless oil (135.0 g). Purity, 90% based on 1HNMR. ¹H NMR (CDCl₃, 300 MHz) δ 7.0 (dd, J=42.4 and 1.5 Hz, 1H), 6.73(dd, J=20.5 and 1.8 Hz, 1H), 3.80 (s, 6H), 3.76 (s, 3H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 5-(1,1-dimethylethyl) 1a-methylester, (+/−)

Sodium hydride (96 mg, 4 mmol) was added to a stirred suspension oftrimethylsulfoxonium chloride (567 mg, 4.4 mmol) in anhydrous DMSO (10mL) under nitrogen. The resultant mixture was stirred at rt for 30-45min and then neat 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid,13-cyclohexyl-3-methoxy-, 10-(1,1-dimethylethyl) 6-methyl ester (1.0, 2mmol) was added in small portions. The suspension was diluted with DMSO(5 mL) and heated at 50° C. for 3-4 h. The reaction mixture was allowedto cool to rt and water was added. A solid separated, which wascollected by filtration and washed with water and then air driedovernight to afford 1.15 g of crude product. This material was purifiedby flash column chromatography (silica gel, 3% MeOH in DCM) to providepure title compound (0.96 g): LC/MS: Retention time 3.816 min; m/e 516(MH⁺). ¹H NMR (400 MHz, CDCl₃): The product was observed to exist asinter-converting rotamers, as evidenced from the compound's NMRspectrum.

The following procedure is an example of a method to effect theresolution of racemiccycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 5-(1,1-dimethylethyl) 1a-methylester, (+/−). A sample ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 5-(1,1-dimethylethyl) 1a-methylester, (+/−)—was dissolved in a mixture of isopropanol and acetonitrile(8:2) to give a final concentration of 20 mg/mL. This mixture wasinjected on a preparative chiral SFC chromatography system using thefollowing conditions: Chiralcel OJ-H column, 4.6×250 mm, 5 μm; MobilePhase: 8% MeOH in CO₂; Temp: 35° C.; Flow rate: 2 mL/min for 16 min; UVmonitored@260 nm; Injection: 54 of 20.0 mg/mL in IPA:ACN (8:2).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a, 5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy, 1a-methyl ester, (+/−)-

TFA (5 mL) was added to a solution of (+/−)8-Cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid, tert-butyl ester (515 mg, 1 mmol) in anhydrous DCM (10 mL). Theresultant solution was stirred at rt for approximately 8 to 12 hr. Thereaction was then evaporated to dryness to afford the title compound(0.47 g, 100%). LC/MS: Retention time 2.245 min; m/e 460 (MH⁺). ¹H NMR(400 MHz, CDCl₃): From the compounds NMR spectrum, the product wasobserved to exist as a mixture of interconverting rotamers.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-5-[[[(methylamino)sulfonyl]amino]carbonyl],methyl ester

A solution of8-Cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (140 mg, 0.31 mmol) and CDI (64 mg, 0.40 mmol) in THF (3 mL) wasstirred for 1 hr at 60° C. N-methylsulfamide (68 mg, 0.62 mmol) and DBU(71.6 mg, 0.47 mmol) were added and the mixture was stirred at 60° C.overnight. The reaction was then poured into cold water, acidified withdilute hydrochloric acid and extracted into ethyl acetate. The extractswere washed sequentially with dilute hydrochloric acid (0.1 N), andbrine, and then dried (anhy. sodium sulfate), filtered and evaporated toprovide the title compound as a brown solid. ESI-MS m/e 552 (MH⁺). Thismaterial was used without further purification.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-5-[[[(methylamino)sulfonyl]amino]carbonyl]

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(methylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester was dissolved in THF, MeOH mixture (2 mL, 2 mL). 2.5 M NaOH(aq.) (1.2 mL, 3 mmol) was then added and the reaction was shaken at 22°C. for 2 hr. The solution was then neutralized with 1M HCl (aq.) (3 mL)and concentrated to remove the organic solvents. The residue wasslurried with H₂O and the solids were collected by filtration, washedwith H₂O and dried to yield compound the title compound (160 mg, 0.30mmol). ESI-MS m/e 538 (MH⁺). This material was used without furtherpurification.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(benzylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-(methoxy)-12-(methoxy)-,methyl ester, (+/−)-

A solution of (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (200 mg, 0.44 mmol) and CDI (92 mg, 0.57 mmol) in THF (5 mL) wasstirred for 1 hr at 60° C. N-benzylsulfamide (164 mg, 0.88 mmol) and DBU(100 mg, 0.66 mmol) were then added and the resultant mixture wasstirred at 60° C. overnight. The reaction was then poured into coldwater, acidified with dilute hydrochloric acid and extracted into ethylacetate. The organic phase was washed hydrochloric acid (0.1 N), brineand dried (sodium sulfate) and evaporated in vacuo to provide the titlecompound as a brown solid. ESI-MS m/e 628 (MH⁺).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-5-[[[[(phenylmethyl)amino]sulfonyl]amino]carbonyl]-,(+/−)-

The title compound was prepared using a similar procedure to thatdescribed for cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid,8-cyclohexyl-5-[[[(methylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid starting from (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid. ESI-MS m/e 613 (MH+), 1H NMR (500 MHz, MeOD) δ ppm 1.22-2.20 (m,13H) 3.27-3.31 (m, 1H) 3.47 (d, J=14.95 Hz, 0.6H) 3.92 (d, J=2.44 Hz,3H) 4.04 (d, 0.4H) 4.31 (d, J=2.75 Hz, 2H) 5.24 (d, 0.4H) 5.48 (d, 0.6H)7.02 (d, 1H) 7.17 (d, J=2.75 Hz, 1H) 7.19-7.35 (m, 5H) 7.39 (t, J=7.48Hz, 2H) 7.45-7.52 (m, 1H) 7.80 (d, J=1.53 Hz, 0.4H) 7.85 (dd, J=8.39,6.87 Hz, 1H) 8.22 (d, J=1.53 Hz, 0.6H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[(cyclopropylsulfonyl)amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+/−)-

A mixture of (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (1 equiv), and carbonyldiimidazole (1.5 equiv) in anhydrous THF washeated at 50° C. for 30 min and allowed to cool to rt. Then 1 equiv ofcyclopropanesulfonamide and 1,8-diazabicyclo[5.4.0]undec-7-ene (2 equiv)were added consecutively. The resultant mixture was stirred at rtovernight. After acidic aqueous workup, the isolated crude product waspurified by prep. HPLC. The intermediate ester was then hydrolyzed using1N NaOH in THF-MeOH to afford the title compound. LC/MS: Retention time:2.030 min; m/e 549 (MH⁺). ¹H NMR (400 MHz, CDCl₃): The product wasobserved to exist as inter-converting rotamers, as evidenced from thecompound's NMR spectrum.

3,8-Diazabicyclo[3.2.1]octane,3-methyl-8-(phenylmethyl)-

Cis-1-Benzyl-2,5-bis(chloromethyl)pyrrolidine hydrochloride (37.5 g,0.13 mol) (Prepared as described in Published PCT patent applicationWO200232902) was suspended in CH₃CN (900 mL) in a 3-neck 5 L roundbottom flask fitted with mechanical stirrer, reflux condenser, andthermometer. The stirred suspension was warmed to 50° C., NaHCO₃ (97 g,1.1 mol) was added, and the suspension was warmed to 70° C. NaI (50 g,0.33 mol) was added and stirred at 70° C. for 5 min, at which point anaddition funnel was affixed atop the condenser. To the addition funnelwas added 48 mL of 40% aqueous MeNH₂ (0.55 mol) in 850 mL of CH₃CN, andthis solution was added dropwise (rate of addition maintained between10-15 ml/min). The addition was complete after 75 min, at which pointthe reaction was cooled to rt., the solids filtered off, and the solventconcentrated to ˜800 mL. The reaction was poured into EtOAc (800 mL) andwashed with 1 N NaOH (2×100 mL). The aqueous phase was re-extracted withEtOAc (2×100 mL), the combined organic phases were dried over Na₂SO₄ andconcentrated. The resulting residue was introduced on to silica gel (620g) and eluted with 2.8% MeOH/0.4% conc. NH₄OH in CHCl₃ (6 L total). Purefractions were collected from 2 L to 4 L. Concentration yielded 8.76 g(32% yield) of the title compound as a brown oil. 1H NMR (400 MHz,CDCl₃) δ ppm 1.79-1.87 (m, 2H) 1.92-1.99 (m, 2H) 2.23 (s, 3H) 2.27-2.37(m, 2H) 2.54-2.63 (m, 2H) 3.10 (s, 2H) 3.52 (s, 2H) 7.20-7.26 (m, 1H)7.30 (t, J=7.30 Hz, 2H) 7.36-7.42 (m, 2H). LC method: Solvent A=10%MeOH/90% H2O/0.1% TFA, Solvent B=90% MeOH/10% H2O/0.1% TFA, Start %B=0%, Final % B=100, Flow Rate=4 ml/min, Gradient time=2 min, Run time=3min, Column: Phenomenex-Luna 10 μm C18 50 mm×3.0 mm, Rt=0.23 min; MS:(ES+) m/z (M+H)+=217.3. An additional 6.1 g of mixed fractions wereobtained from the column (>80% pure by 1H NMR integration).

3,8-Diazabicyclo[3.2.1]octane, 3-methyl-, dihydrochloride

N-methyl-N-benzylbicyclodiamine, (14.22 g, 65.7 mMol) was dissolved in650 ml of methanol and 17 ml of 12M aqueous hydrochloric acid was added.The solution was placed in a 2 L Parr bottle under nitrogen and 3.66 gof 20% palladium hydroxide on carbon added to the reaction. The mixturewas placed on a Parr shaker under 60 psig of hydrogen for 17 hours. Thereaction was judged complete by TLC analysis (Silica Gel plate elutedwith a 10 parts by volume solution of 2M ammonia in methanol dissolvedin 90 parts by volume of chloroform). The reaction was filtered througha plug of ceilite, which was then rinsed sequentially with water andmethanol. The combined filtrates were concentrated in vacuuo andmethanol and benzene added until a homogenous solution was obtained. 75mL of 2.0M hydrochloric acid in diethyl ether was then added. Volatileswere removed from the product solution in vacuuo. A pale yellow solidwas eventually obtained by repeated azetroping of water from the productsolution using a methanol/benzene mixture. The solid product,3-methyl-3,8-diazabicyclo[3.2.1]octane was dried in vacuuo overnight toobtain 11.98 g (91%) of a hygroscopic solid. The product was removedfrom the flask and bottled in a glove bag under nitrogen due to itshygroscopic nature. ¹H NMR (500 MHz, DMSO-D6) δ ppm 1.96-2.14 (m, 2H)2.34 (d, J=8.24 Hz, 2H) 2.66 (s, 3H) 3.46 (d, J=11.90 Hz, 2H) 3.58 (s,3H, contains H2O) 4.17 (s, 2H) 9.92 (s, 1H) 10.21 (s, 1H) 11.39 (s, 1H);¹³C NMR (126 MHz, DMSO-D6) δ ppm 24.04 (s, 1C) 43.49 (s, 1C) 52.50 (s,1C) 54.47 (s, 1C).

3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid, phenylmethyl ester and3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane

Triethylamine (1.44 mL, 10.363 mmol) was added to a solution of8-boc-3,8-diaza-bicyclo[3.2.1]ocatane (2.0 g, 9.421 mmol) in CH₂Cl₂ (20mL), Benzyl chloroformate (1.46 mL, 10.363 mmol) was added dropwise at0° C. and the reaction mixture was stirred at 0° C. for 0.5 hr, thenallowed to warm to rt. and stirring was continued for 3 days. Thereaction mixture was then quenched with water and acidified with 1N HClsolution. The organic layer was separated, washed with brine, dried(MgSO₄) and concentrated to give a colorless thick oil as the crudeproduct. 70 mg of this material was then dissolved in 1,2-dichloroethane(2 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred atrt. for 2 hr. The solvent and TFA were then evaporated to give a mixtureof the two title compounds as a colorless thick oil.

General procedure for making sulfonamides. A mixture of acid (1 equiv)and carbonyldiimidazole (1.5 equiv) in an. THF was heated at 50° C. for30 min and allowed to cool to rt. Then 1 equiv of either sulfamide(R═NR₂) or sulfonamide (R=alkyl or aryl) and DBU (2 equiv) were addedconsecutively. The resultant mixture was stirred at rt overnight. Afteracidic aqueous workup, isolated crude product was purified by prep. HPLCto afford the title intermediates.

General procedure for making acids. Methyl esters hydrolyzed using 1NNaOH in THF-MeOH.

Neat CDI (0.049 g, 0.302 mmol) was added to stirred solution of the acid(0.092 g, 0.200 mmol) in THF (1 ml) and the mixture was heated at 50° C.for 30 min and then allowed to cool to rt. ThenN-cyclopropyl-N-methylsulfamide (0.0451 g, 0.300 mmol) and DBU (0.060ml, 0.400 mmol) were added consecutively. The mixture sonicated for 1-2hand then stirred overnight at rt. Reaction was quenched with MeOH (0.5ml) and then acidified with 1N HCl and extracted with EtOAc (2×25 mL),washed with water, brine and dried (Na₂SO₄). Crude product (0.123 g) waspurified by silica gel flash chromatography (5% MeOH in DCM) to affordthe expected product The product as a off-white solid (0.101 g 85%).

1N NaOH (2 mL, 2.000 mmol) was added to stirred solution of the methylester (0.098 g, 0.166 mmol) in THF-MeOH under nitrogen. The mixture wasstirred at rt for 2 h and then acidified with 1N HCl (3 ml), extractedwith EtOAc (2×25 ml), washed with water, brine and dried (MgSO₄).Evaporation of solvents gave the acid as an off-white solid (0.0942 g,98%). LC/MS: m/e 578 (MH+). LC/MS method: Start % B: 0, Final % B: 100;Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 ml/min; Wavelenth:220; Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid; Solvent B:10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column: XBridge 4.6×50 mmS5.

t-Butanol (1.35 mL, 14 mmol) was added dropwise to the solution of CSI(1.24 mL, 14 mmol) of CH₂Cl₂ (10 mL) at 0° C. The generated solution wasstirred for 2 h at 0° C. A solution of N-methylpropan-2-amine (1.57 ml,14.13 mmol) and TEA (2.167 ml, 15.54 mmol) in CH₂Cl₂ (3 ml) was addeddropwise. The generated reaction mixture was stirred for 2 h at r.t. Thereaction mixture was diluted with EtOAc and washed with cold 1N HCl,brine, dried (MgSO₄), removed the solvent and the residue was purifiedby Biotage 40M column (EtOAc-MeOH (90-10)/hexane 5% to 100%) to affordthe product as a colorless gel (2.3 g, 65%) 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.19 (d, J=6.55 Hz, 6H) 1.49 (s, 9H) 2.90 (s, 3H)4.05-4.26 (m, 1H) 7.02 (br. s., 1H).

To tert-butyl N-isopropyl-N-methylsulfamoylcarbamate (2.3 g, 9.12 mmol)was added cold HCl (6 mL, 24.00 mmol) and stirred at room temperaturefor 2 h, removed the solvent to afford the product as a solid in lighttan(1.38 g, 99%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.80Hz, 5H) 2.72 (s, 3H) 4.16 (dt, J=13.53, 6.70 Hz, 1H) 4.43 (br. s., 1H).

The product (0.261 g, 81%) was made from the acid (0.25 g, 0.54 mmol)and amine using CDI and DBU. LC-MS retention time: 3.635 min; MS m/z(M+H) 594. H NMR showed compound existed as rotamers (˜4/3). LC/MSmethod: Start % B: 0, Final % B: 100; Gradient time: 3 min; Stop time: 4min; Flow rate: 4 ml/min; Wavelenth: 220; Solvent A: 10% MeOH/90%H₂O/0.1% Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1%Trifluoroacetic Acid; Column: XBridge 4.6×50 mm S5.

The acid (0.22 g, 87%) was made from the ester (0.258 g, 0.435 mmol)using NaOH in THF/MeOH. The acid was isolated as a pale yellow solid.LC-MS retention time: 3.608 min; MS m/z (M+H) 580. LC/MS method: Start %B: 0, Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate:4 ml/min; Wavelength: 220; Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid; Column: XBridge 4.6×50 mm S5. 1H NMR existed rotomers (˜1/2). Themajor isomer: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, J=6.30 Hz,1H) 1.08-2.15 (m, 17H) 2.63-2.80 (m, 1H) 2.84-2.96 (m, 1H) 3.04 (s, 3H)3.84 (s, 3H) 4.03 (d, J=14.86 Hz, 1H) 4.22-4.41 (m, 1H) 5.35 (d, J=15.11Hz, 1H) 6.86 (dd, J=8.44, 2.39 Hz, 1H) 6.98 (d, J=2.27 Hz, 1H) 7.20 (d,J=8.56 Hz, 1H) 7.67 (d, J=8.31 Hz, 1H) 7.81-7.89 (m, 1H) 8.10 (s, 1H).

General procedure for making amides for some examples. Acid derivatives(1 equiv) were combined with corresponding amine (1.2 equiv),triethylamine (2-3 equiv) and TBTU (1.3 equiv) in anh. DMF and stirredat rt for 1-2 h until completion of the amide coupling. Isolated crudeproducts were purified by prep. HPLC to provide the desired amides.

Example 1

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(+/−)-

TBTU (43.7 mg, 0.136 mmol) and DIPEA (0.095 mL, 0.544 mmol) were addedto a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(50mg, 0.0906 mmol) in DMSO (2.0 mL). The reaction mixture was stirred atrt for 15 min. 3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride{J & W PharmLab, LLC Morrisville, Pa. 19067-3620}. (27.1 mg, 0.136 mmol)was then added and the reaction mixture was stirred at rt for 3 hr. Itwas then concentrated and the residue was purified by preparativereverse phase HPLC to give the final product as a yellow solid, (32 mg,46% yield). MS m/z 660 (MH⁺), Retention time: 2.445 min 1H NMR (300 MHz,MeOD) δ ppm 0.20 (m, 0.23H) 1.11-2.25 (m, 15.77H) 2.58 (m, 0.23H) 2.69(m, 0.77H) 2.75-3.11 (m, 10H) 3.28-3.75 (m, 5H) 3.91 (s, 2.31H) 3.92 (s,0.69H) 4.15-4.37 (m, 1H) 4.68 (m, br, 1H) 4.94-5.00 (m, 0.23H) 5.16 (d,J=15.00 Hz, 0.77H) 7.00-7.09 (m, 1H) 7.18 (d, J=2.56 Hz, 0.23H) 7.21 (d,J=2.56 Hz, 0.77H) 7.33 (d, J=8.41 Hz, 0.77H) 7.35 (d, J=8.42 Hz, 0.23H)7.57 (dd, J=8.42, 1.46 Hz, 0.77H) 7.62 (dd, J=8.78, 1.46 Hz, 0.23H) 7.91(d, J=8.42 Hz, 0.77H) 7.93 (d, J=8.42 Hz, 0.23H) 8.00 (s, 0.77H) 8.07(s, 0.23H).

Example 2

3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid,3-[[8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxycycloprop[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl]carbonyl]-,1,1-dimethylethyl ester, (+/−)-

TBTU (131 mg, 0.408 mmol) and DIPEA (0.237 mL, 1.36 mmol) were added toa solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(150mg, 0.272 mmol) in DMSO (4.0 mL). The reaction mixture was stirred at rtfor 15 min. 8-Boc-3,8-diaza-bicyclo[3.2.1]octane (86.7 mg, 0.408 mmol)was then added and the reaction mixture was stirred at rt overnight. Itwas then concentrated and the residue was purified by preparativereverse phase HPLC to give the title product as a light yellow solid,(110 mg, 54% yield). MS m/z 746 (MH⁺), Retention time: 3.040 min. 1H NMR(300 MHz, MeOD) δ ppm 0.17 (m, 0.25H) 1.08 (m, 0.25H) 1.17-2.28 (m,24.5H) 2.38-3.12 (m, 8H) 3.43-4.43 (m, 10H) 4.76-4.85 (m, 0.25H)4.96-5.19 (m, 0.75H) 7.02 (dd, J=8.60, 2.38 Hz, 1H) 7.17 (d, J=2.19 Hz,0.25H) 7.20 (d, J=2.20 Hz, 0.75H) 7.26-7.39 (m, 1H) 7.49-7.70 (m, 1H)7.80-8.00 (m, 1.75H) 8.12 (s, 0.25H).

Example 3

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1a-(3,8-diazabicyclo[3.2.1]oct-3-ylcarbonyl)-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-,(+/−)-

TFA (2 mL) was added to a solution of (+/−)3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid,3-[[8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxycycloprop[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl]carbonyl]-,1,1-dimethylethyl ester (98 mg, 0.131 mmol) in 1,2-dichloroethane (3mL). The reaction mixture was stirred at rt. for 2 hr. It was thenconcentrated to give the desired product as a brownish colored solid,(100 mg, 100% yield). MS m/646 (MH⁺), Retention time: 2.478 min. 1H NMR(500 MHz, MeOD) δ ppm 0.24 (m, 0.28H) 1.14 (m, 0.28H) 1.19-2.23 (m,15.22H) 2.57 (m, 0.28H) 2.69 (m, 0.72H) 2.81-3.09 (m, 8H) 3.30-3.40 (m,1H) 3.67 (d, J=15.87 Hz, 0.72H) 3.91 (s, 2.16H) 3.93 (s, 0.84H)3.90-4.27 (m, 4.28H) 4.88-4.91 (m, 0.28H) 5.11 (d, J=15.56 Hz, 0.72H)7.00-7.09 (m, 1H) 7.19 (d, J=2.75 Hz, 0.28H) 7.21 (d, J=2.14 Hz, 0.72H)7.34 (d, J=8.54 Hz, 0.72H) 7.37 (d, J=8.55 Hz, 0.28H) 7.59 (dd, J=8.55,1.53 Hz, 0.72H) 7.63 (dd, J=8.39, 1.37 Hz, 0.28H) 7.92 (d, J=8.55 Hz,0.72H) 7.94-7.99 (m, 1H) 8.10 (s, 0.281H).

Example 4

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-,(+/−)-

To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1a-(3,8-diazabicyclo[3.2.1]oct-3-ylcarbonyl)-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-(54mg, 0.071 mmol) in methanol (3 mL), paraformaldehyde (6.4 mg, 0.213mmol), ZnCl₂ (29 mg, 0.213 mmol) and Na(CN)BH₃ (13.4 mg, 0.213 mmol)were added. The resultant mixture was heated at 60° C. for 2 hr, andthen cooled to rt. The solid present was removed by filtration, and thefiltrate was concentrated under vacuum and the residue purified bypreparative reverse phase HPLC to give the title compound as a lightyellow colored solid, (37 mg, 67% yield). MS m/660 (MH⁺), Retentiontime: 2.495 min. 1H NMR (500 MHz, MeOD) δ ppm 0.21 (m, 0.3H) 1.13 (m,0.3H) 1.18-2.22 (m, 15.4H) 2.58 (m, 0.3H) 2.68 (m, 0.7H) 2.76-3.11 (m,11H) 3.32-3.37 (m, 1H) 3.63 (d, J=15.56 Hz, 0.7H) 3.82-4.32 (m, 7.3H)4.88-4.92 (m, 0.3H) 5.08 (d, J=15.56 Hz, 0.7H) 7.00-7.08 (m, 1H) 7.18(d, J=2.14 Hz, 0.3H) 7.21 (d, J=2.14 Hz, 0.7H) 7.32 (d, J=8.55 Hz, 0.7H)7.35 (d, J=8.55 Hz, 0.3H) 7.57 (d, J=7.93 Hz, 0.7H) 7.62 (dd, J=8.39,1.37 Hz, 0.3H) 7.91 (d, J=8.55 Hz, 0.7H) 7.93-7.99 (m, 1H) 8.09 (s,0.3H).

Example 5

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[[8-(1-methylethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]carbonyl]-,(+/−)-

To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1a-(3,8-diazabicyclo[3.2.1]oct-3-ylcarbonyl)-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-(40mg, 0.071 mmol) in methanol (3 mL), acetone (1 mL), ZnCl₂ (29 mg, 0.213mmol) and Na(CN)BH₃ (13.4 mg, 0.213 mmol) were added. The reactionmixture was heated at 60° C. overnight, and then cooled to rt. The solidpresent was removed by filtration, and the filtrate was concentratedunder vacuum and the residue purified by preparative reverse phase HPLCto give the title compound as a light yellow colored solid. (29 mg, 69%yield). MS m/688 (MH⁺), Retention time: 2.477 min. 1H NMR (300 MHz,MeOD) δ ppm 0.20 (m, 0.23H) 1.12 (m, 0.23H) 1.18-2.41 (m, 21.54H)2.51-3.18 (m, 10H) 3.64 (d, J=15.37 Hz, 0.77H) 3.79-4.51 (m, 8.23H)4.81-4.88 (m, 0.23H) 5.07 (d, J=14.27 Hz, 0.77H) 6.99-7.08 (m, 1H)7.17-7.23 (m, 1H) 7.28-7.36 (m, 1H) 7.57 (dd, J=8.42, 1.10 Hz, 0.77H)7.61 (dd, J=8.42, 1.47 Hz, 0.23H) 7.83-8.00 (m, 1.77H) 8.09 (s, 0.23H).

Example 6

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(1aR,12bS)-

To a solution of (−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(204mg, 0.37 mmol) in DMSO (8.0 mL), TBTU (178 mg, 0.555 mmol) and DIPEA(0.39 mL, 2.22 mmol) were added. The reaction mixture was stirred at rtfor 15 min. Then 3-methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride(111 mg, 0.555 mmol) was added and the reaction mixture was stirred atrt for 2 hr. It was then concentrated and the residue was purified bypreparative reverse phase HPLC to give a yellow solid as final TFA salt.(265 mg, 92% yield). Average Specific Rotation: −53.56° Solvent, MeOH.;Wavelength 589 nm; 50 cm cell. MS m/z 660 (MH), Retention time: 3.035min. ¹H NMR (300 MHz, MeOD) δ ppm 0.20 (m, 0.23H) 1.11-2.25 (m, 15.77H)2.58 (m, 0.23H) 2.69 (m, 0.77H) 2.75-3.11 (m, 10H) 3.28-3.75 (m, 5H)3.91 (s, 2.31H) 3.92 (s, 0.69H) 4.15-4.37 (m, 1H) 4.68 (m, br, 1H)4.94-5.00 (m, 0.23H) 5.16 (d, J=15.00 Hz, 0.77H) 7.00-7.09 (m, 1H) 7.18(d, J=2.56 Hz, 0.23H) 7.21 (d, J=2.56 Hz, 0.77H) 7.33 (d, J=8.41 Hz,0.77H) 7.35 (d, J=8.42 Hz, 0.23H) 7.57 (dd, J=8.42, 1.46 Hz, 0.77H) 7.62(dd, J=8.78, 1.46 Hz, 0.23H) 7.91 (d, J=8.42 Hz, 0.77H) 7.93 (d, J=8.42Hz, 0.23H) 8.00 (s, 0.77H) 8.07 (s, 0.23H).

An alternate procedure for the synthesis ofcycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(1aR,12bS)-rel-(−)—is provided below. To a mixture of (−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(25.2g, 45.68 mmol) and 3-methyl-3,8-diazabicyclo-[3.2.1]octanedihydrochloride (10.0 g, 50.22 mmol) in anhydrous MeCN (300 mL) wasadded DIPEA (23.62 g, 182.72 mmol) under N₂. After 15 min, TBTU (16.12g, 50.22 mmol) was added. The reaction solution was stirred for 30 minunder N₂. The HPLC indicated the disappearance of starting material. Thesolvent in the solution was evaporated to give a foam. This wasdissolved in EtOAc (2.5 L), washed with H₂O (1.5 L), H₂O/brine (8:2)(1.5 L), brine (1.5 L), dried over Na₂SO₄ and evaporated to give 28.8 gof crude product. This solid was pooled with 45.4 g of material obtainedfrom five separated reactions to afford a total of 74.2 g of crudeproduct. This was passed through a pad of silica gel (E. Merck 230-400mesh, 1 kg), eluting with MeOH/CH₂Cl₂ (2.5:97.5). After evaporation, itgave a foam, which was treated with EtOAc and hexane to turn into asolid. After drying at 50° C. under vacuum for 7 h, the GC analysisindicated it has 1.4% each of EtOAc and hexane. After further drying at61-64° C., the GC analysis indicated it still has 1.0% of hexane and1.4% of EtOAc. The product was dissolved in Et₂O and slowly evaporatedin vacuum three times, dried at 60° C. under vacuum for 3 h to give 68.3g. This was washed with H₂O (900 mL) and redried at 68° C. under vacuumfor 7 h to give 67.1 g (77% yield) of the compound of example 6. The GCanalysis indicated it has 0.97% of Et₂O. HPLC conditions column: CadenzaCD-C18 3×250 mm; UV: 257 and 220 nm; 25° C.; flow rate: 0.5 mL/min;gradient time: 38 min, 0-80% B (0-35 min) and 80% B (35-38 min); solventA: 25 nM CH₃COONH₄ at pH 4.7 in water, solvent B: MeCN. HPLC purity99.7% (Rt 26.54 min); Chiral HPLC conditions column: Regis (S,S)Whelk-O1 250×4.6 mm; UV 258 nm; 35° C.; flow rate 2.0 mL/min; mobilephase CO₂/MeOH; gradient time 20 min, 30% MeOH (0-1 min), 30-48% MeOH(1-19 min), 48% MeOH (19-20 min). Chiral HPLC purity>99.8% (Rt 16.60min); LC/MS (ES⁺) 660.36 (M+H, 100); HRMS: calcd. 660.3220, found660.3197; [α]_(D) ^(25C)−79.66° (c 1.06, MeOH); Anal. Calcd forC₃₆H₄₅N₅O₅S.0.6H₂O.0.09 Et₂O: C, 64.53; H, 7.00; N, 10.35; S, 4.74; H₂O,1.51; Et₂O, 0.97. Found: C, 64.50; H, 7.12; N, 10.41; S, 5.14; H₂O,1.52; Et₂O, 0.97. The absolute stereochemistry ofcycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(1aR,12bS)-rel-(−)—is as drawn above, and was determined from an x-raycrystal structure obtained on the (R)-camphorsulfonic acid salt.

Additionally, the following salts were prepared: hydrochloride,phosphate, acetate, sulfate, camsylate, sodium, calcium, and magnesium.The hydrochloride salt had the following characteristics. DSC: small,broad endotherm from 25° C. to 75° C., and potential melt/degradationendotherm with peak at temperatures ranging between 253° C. and 258° C.;TGA: Early weight loss from 25° C. to 75° C. ranging between 0.003% and1.5%, and degradation weight loss starting at approximately 200° C.

Example 7

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-(cyclopropylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(+/−)-

(+/−)8-cyclohexyl-5-(cyclopropylsulfonylcarbamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a-carboxylicacid (1 equiv) was combined with 3-methyl-3,8-diazabicyclo[3.2.1]octane(1.2 equiv), triethylamine (3 equiv) and TBTU (1.3 equiv) in anhydrousDMF and stirred at rt for approximately 2 h until the reaction wasobserved to go to completion by LCMS analysis. The product was thenisolated by preparative reverse phase HPLC to provide the mono TFA saltof the desired title compound as a beige solid. LC/MS: Retention time:2.986 min; m/e 657 (MH⁺). The compound was observed to exist asinter-converting rotamers by ¹H NMR (400 MHz, CHLOROFORM-D): δ ppm0.22-0.36 (m, 1H)H), 1.09-1.20 (m, J=8.06 Hz, 3H), 1.18-1.30 (m, 2H)1.29-1.48 (m, 5H), 1.48-1.67 (m, 1H), 1.68-1.86 (m, 3H), 1.87-2.09 (m,5H), 2.11-2.40 (m, 1H), 2.42-2.67 (m, 1H), 2.67-2.88 (m, J=4.78 Hz, 1H),2.86-3.02 (m, 2H), 3.02-3.28 (m, 2H), 3.42-3.55 (m, 1H), 3.55-3.77 (m,2H), 3.83-3.92 (m, 3H), 3.93-4.15 (m, 1H), 4.28-4.58 (m, 1H), 4.61-4.99(m, J=106.26 Hz, 1H), 5.04-5.26 (m, 1H), 6.90-7.03 (m, 1H), 7.07-7.15(m, J=2.52 Hz, 1H), 7.27-7.36 (m, 1H), 7.42-7.68 (m, 1H), 7.82-7.96 (m,J=8.56 Hz, 1H), 8.01-8.18 (m, 1H).

Example 8

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[[3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-,(+/−)-

To a solution ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(40mg, 0.0725 mmol) in DMSO (1.0 mL), TBTU (35 mg, 0.109 mmol) and DIPEA(0.076 mL, 0.435 mmol) were added. The reaction mixture was stirred atrt. for 15 min. The mixture from the preparation of benzyl3,8-diazabicyclo[3.2.1]octane-3-carboxylate described above was thenadded and the reaction was stirred at rt overnight. It was thenconcentrated and the residue was purified by preparative reverse phaseHPLC to give the product as a light yellow solid, (12.5 mg, 20% yield).MS m/z 736 (MH⁺), Retention time: 2.631 min. 1H NMR (500 MHz, MeOD) δppm 0.20 (m, 0.16H) 1.11-2.25 (m, 15.84H) 2.57 (m, 0.16H) 2.70 (m,0.84H) 2.85 (m, 0.16H) 2.80-3.60 (m, 11.84H) 3.65 (d, J=15.26 Hz, 0.84H)3.92 (s, 3H) 4.22 (d, J=14.95 Hz, 0.16H) 4.33-4.76 (m, 3H) 4.96 (m,0.16H) 5.08-5.33 (m, 0.84H) 6.97-7.10 (m, 1H) 7.17 (d, J=2.44 Hz, 0.16H)7.22 (d, J=2.44 Hz, 0.84H) 7.28-7.42 (m, 1H) 7.43-7.74 (m, 6H) 7.87-7.96(m, 1H) 7.99-8.19 (m, 1H).

Example 9

3,8-Diazabicyclo[3.2.1]octane-3-carboxylic acid,8-[[8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxycycloprop[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl]carbonyl]-,phenylmethyl ester, (+/−)-

To a solution ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(40mg, 0.0725 mmol) in DMSO (1.0 mL), TBTU (35 mg, 0.109 mmol) and DIPEA(0.076 mL, 0.435 mmol) were added. The reaction mixture was stirred atrt for 15 min. The mixture from the preparation of benzyl3,8-diazabicyclo[3.2.1]octane-3-carboxylate was then added and thereaction was stirred at rt. overnight. It resultant mixture was thenconcentrated in-vacuo and the residue was purified by preparativereverse phase HPLC to give the product as a light yellow solid, (42 mg,74% yield). MS m/z 780 (MH⁺), Retention time: 3.070 min. 1H NMR (500MHz, MeOD) δ ppm 0.14 (m, 0.22H) 1.06-2.20 (m, 15.78H) 2.51 (m, 0.22H)2.58-3.23 (m, 9.78H) 3.54-4.07 (m, 6.78H) 4.16 (d, J=14.65 Hz, 0.22H)4.31-4.59 (m, br, 1H) 4.96 (m, 0.22H) 5.02-5.23 (m, 2.78H) 6.94-7.07 (m,1H) 7.16 (d, J=2.44 Hz, 0.22H) 7.21 (s, 0.78H) 7.26-7.45 (m, 6H)7.50-7.65 (m, 1H) 7.82-8.04 (m, 1.78H) 8.10 (s, 0.22H).

Example 10

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1a-(3,8-diazabicyclo[3.2.1]oct-8-ylcarbonyl)-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-,(+/−)-

To a solution of 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid,8-[[8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxycycloprop[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl]carbonyl]-,phenylmethyl ester (360 mg, 0.462 mmol) in methanol/ethyl acetate (20mL/20 mL), 10% Pd on carbon (40 mg) was added. The reaction mixture wasstirred under a hydrogen atmosphere (1 atm) overnight. The mixture thenfiltered through celite, and the filtrand washed with methanol and ethylacetate. The combined filtrates were concentrated to give the product asa yellow solid, (275 mg, 92% yield). MS m/z 646 (MH⁺), Retention time:2.983 min. 1H NMR (500 MHz, MeOD) δ ppm 0.20 (m, 0.2H) 1.12-2.29 (m,15.8H) 2.52-2.86 (m, 1.2H) 2.99 (m, 0.8H) 3.02 (s, 4.8H) 3.03 (s, 1.2H)3.09-3.49 (m, 5H) 3.68 (d, J=15.26 Hz, 0.8H) 3.91 (s, 2.4H) 3.92 (s,0.6H) 4.03-4.26 (m, 0.4H) 4.62-4.85 (m, 1H) 5.17 (d, J=13.71 Hz, 0.8H)6.99-7.11 (m, 1H) 7.19 (s, 0.2H) 7.23 (s, 0.8H) 7.32-7.40 (m, 1H) 7.59(d, J=8.24 Hz, 0.8H) 7.63 (d, J=8.24 Hz, 0.2H) 7.89-7.96 (m, 1H) 7.98(s, 0.8H) 8.09 (s, 0.2H).

Example 11

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1a-[(3-ethyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1,1a,2,12b-tetrahydro-11-methoxy-,(+/−)-

To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-(30mg, 0.0465 mmol) in methanol (2 mL), acetaldehyde (0.013 mg, 0.232mmol), ZnCl₂ (19 mg, 0.14 mmol) and Na(CN)BH₃ (8.8 mg, 0.14 mmol) wereadded. The resultant mixture was stirred at rt overnight, during whichtime a precipitate formed. This solid was removed by filtration, and thefiltrate concentrated under vacuum. The residue was then purified bypreparative reverse phase HPLC to provide the TFA salt of the titlecompound as a light yellow solid, (35 mg, 96% yield). MS m/z 674 (MH⁺),Retention time: 3.013 min. 1H NMR (500 MHz, MeOD) δ ppm 0.22 (m, 0.16H)1.09-2.29 (m, 18.84H) 2.59 (m, 0.16H) 2.70 (m, 0.84H) 2.86 (m, 0.16H)2.97-3.03 (m, 5.88H) 3.03 (s, 0.96H) 3.11-3.81 (m, 7H) 3.92 (s, 2.52H)3.93 (s, 0.48H) 4.22 (d, J=14.95 Hz, 0.16H) 4.39 (s, br, 0.84H)4.60-4.85 (m, 1.16H) 5.20 (d, J=14.64 Hz, 0.84H) 7.01-7.09 (m, 1H) 7.20(d, J=2.75 Hz, 0.16H) 7.22 (d, J=2.44 Hz, 0.84H) 7.33-7.38 (m, 1H) 7.59(dd, J=8.39, 1.37 Hz, 0.84H) 7.63 (dd, J=8.55, 1.53 Hz, 0.16H) 7.90-7.96(m, 1H) 8.02 (s, 0.84H) 8.09 (s, 0.16H).

Example 12

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[[3-(1-methylethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-,(+/−)-

To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-(30mg, 0.0465 mmol) in methanol (2 mL), acetone (0.010 mg, 0.14 mmol) andZnCl₂ (19 mg, 0.14 mmol) were added. The reaction mixture was heated at50° C. for 1 hr. Then Na(CN)BH₃ (8.8 mg, 0.14 mmol) was added, and thereaction was maintained at 50° C. overnight, during which time aprecipitate formed. This material was removed by filtration, and thefiltrate was then concentrated in-vacuo. The resultant residue was thenpurified by Preparative HPLC column to give the TFA salt of the titlecompound as a light yellow solid, (35 mg, 94% yield). MS m/z 688 (MH⁺),Retention time: 3.011 min. 1H NMR (500 MHz, MeOD) δ ppm 0.21 (m, 0.19H)1.11-2.24 (m, 21.81H) 2.58 (m, 0.19H) 2.72 (m, 0.81H) 2.85 (m, 0.19H)2.93-3.03 (m, 5.67H) 3.03 (s, 1.14H) 3.14-3.73 (m, 6H) 3.91 (s, 2.43H)3.93 (s, 0.57H) 4.22 (d, J=14.95 Hz, 0.19H) 4.39 (s, br, 0.81H)4.58-4.80 (m, br, 1H) 4.84 (m, 0.19H) 5.19 (d, J=15.26 Hz, 0.81H)6.99-7.09 (m, 1H) 7.20 (d, J=2.44 Hz, 0.19H) 7.23 (d, J=2.44 Hz, 0.81H)7.31-7.39 (m, 1H) 7.58 (d, J=8.55 Hz, 0.81H) 7.63 (d, J=8.55 Hz, 0.19H)7.93 (d, J=8.24 Hz, 1H) 8.01 (s, 0.81H) 8.11 (s, 0.19H).

Example 13

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1a-[[-(cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-,(+/−)-

To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-(20mg, 0.031 mmol) in methanol (2 mL), cycloporpanecarboxaldehyde (0.007mg, 0.093 mmol), ZnCl₂ (12.7 mg, 0.093 mmol) and Na(CN)BH₃ (5.8 mg,0.093 mmol) were added. The mixture was stirred at rt. for 2 hr, afterwhich an insoluble solid was removed by filtration. The filtrate wasconcentrated in-vacuo, and the resultant residue purified by preparativereverse phase HPLC to give the TFA salt of the title compound as lightyellow solid, (10 mg, 40% yield). MS m/z 700 (MH⁺), Retention time:3.033 min. 1H NMR (500 MHz, MeOD) δ ppm 0.21 (m, 0.18H) 0.47 (s, br, 2H)0.69-0.85 (m, 2H) 0.93-2.29 (m, 16.82H) 2.58 (m, 0.18H) 2.71 (m, 0.82H)2.86 (m, 0.18H) 2.94-3.80 (m, 13.82H) 3.91 (s, 2.46H) 3.93 (s, 0.54H)4.23 (d, J=14.95 Hz, 0.18H) 4.41 (s, br, 0.82H) 4.61-4.79 (m, 1H) 4.98(m, 0.18H) 5.19 (d, J=14.35 Hz, 0.82H) 7.01-7.09 (m, 1H) 7.19 (d, J=2.75Hz, 0.18H) 7.22 (d, J=2.44 Hz, 0.82H) 7.32-7.39 (m, 1H) 7.58 (d, J=8.24Hz, 0.82H) 7.63 (d, J=8.24 Hz, 0.18H) 7.90-7.96 (m, 1H) 8.02 (s, 0.82H)8.09 (s, 0.18H).

Example 14

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,1a-[(3-acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-,(+/−)-

TBTU (15 mg, 0.0465 mmol) and DIPEA (0.027 mL, 0.155 mmol) were added toa solution of acetic acid (3 mg, 0.0465 mmol) in DMSO (1.0 mL), and themixture was stirred at rt for 15 min. (+/−)Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-(20mg, 0.031 mmol) was then added and the reaction was stirred at rtovernight. It was then concentrated, and the residue was purified byPreparative HPLC column to provide the title compound as a light yellowsolid, (7 mg, 33% yield). MS m/z 688 (MH⁺), Retention time: 3.278 min.1H NMR (500 MHz, MeOD) δ ppm 0.18 (m, 0.2H) 1.07-2.27 (m, 18.8H) 2.55(m, 0.2H) 2.72 (m, 0.8H) 2.86 (m, 0.2H) 2.95-3.08 (m, 6.8H) 3.15-3.78(m, 5H) 3.91 (s, 2.4H) 3.93 (s, 0.6H) 4.05-4.29 (m, 1H) 4.40-4.59 (m,1H) 4.93 (m, 0.2H) 5.16 (m, 0.8H) 6.99-7.10 (m, 1H) 7.19 (m, 0.2H) 7.23(d, J=2.14 Hz, 0.8H) 7.30-7.41 (m, 1H) 7.59 (d, J=8.85 Hz, 0.8H) 7.64(d, J=8.24 Hz, 0.2H) 7.86-8.06 (m, 1.8H) 8.13 (s, 0.2H).

Example 15

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[[3-(2-pyridinyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-,(+/−)-

In a microwave reaction tube, (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-(20mg, 0.031 mmol), Pd₂(dba)₃ (0.6 mg, 2 mol %),1,3-bis(diphenylphosphino)propane (0.5 mg, 4 mol %), sodium t-butoxide(8.9 mg, 0.093 mmol) and 2-bromopyridine (0.006 mL, 0.062 mmol) wereadded under nitrogen. The reaction tube was then sealed and dioxane (1mL) was added, and the reaction mixture was then heated at 70° C. in anoil bath overnight. The reaction was then filtered and concentrated, andthe residue was purified by Preparative HPLC column to give the TFA saltof the title compound as an off-white solid, (2.2 mg, 7.5% yield). MSm/z 723 (MH⁺), Retention time: 3.048 min. 1H NMR (500 MHz, MeOD) δ ppm0.25 (m, 0.2H) 1.11-2.23 (m, 15.8H) 2.60 (m, 0.2H) 2.76 (m, 0.8H)2.79-3.10 (m, 7H) 3.13-4.00 (m, 8H) 4.27 (d, J=15.26 Hz, 0.2H) 4.46 (s,br, 0.8H) 4.63-4.81 (m, 1H) 4.99 (m, 0.2H) 5.26 (d, J=15.26 Hz, 0.8H)7.02-7.16 (m, 2H) 7.20-7.27 (m, 1H) 7.32-7.68 (m, 3H) 7.77 (d, J=7.93Hz, 0.2H) 7.85-8.18 (m, 3.8H).

Example 16

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-11-(phenylmethoxy)-,(+/−)-

(+/−) Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-(phenylmethoxy)-,(496 mg, 0.79 mMol) was dissolved in 7 ml of DMF and TBTU (392 mg, 1.22mMol) added and the reaction was stirred under nitrogen for 1 hour atroom temperature after which DMAP (525 mg, 4.29 mMol) was added followedby 3-methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (196 mg, 0.98mMol). The reaction was stirred at room temperature under a nitrogenatmosphere for 17 hours and then poured in to 100 ml of water. Theaqueous mixture was extracted with ethyl acetate. The organic extractwas washed twice with water, then brine and dried over magnesiumsulfate. Removal of volatiles in vacuuo gave 615 mg of crude productwhich was adsorbed onto 1.5 g of silica gel and chromatographed on 18 gof silica gel eluting with 3% methanol in dichloromethane. The pureproduct fractions combined and volatiles removed in vacuuo to yield 216mg (37%) of a nearly colorless amorphous solid. 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 0.27 (t, J=5.80 Hz, 0.4H) 1.14-1.30 (m, 2.9H)1.30-1.48 (m, 3.7H) 1.57 (d, J=15.26 Hz, 2.3H) 1.63-1.87 (m, 11.2H)1.85-2.20 (m, 8.4H) 2.30 (s, 1.3H) 2.39 (s, 0.9H) 2.69 (s, 1.2H) 2.79(s, 1.2H) 2.85-3.01 (m, 1.9H) 3.01-3.11 (m, 6.0H) 3.25-3.51 (m, 1.8H)3.59 (d, J=15.26 Hz, 1.2H) 4.14 (d, J=14.95 Hz, 0.4H) 4.40 (s, 0.9H)4.75 (d, J=13.73 Hz, 0.4H) 5.07-5.21 (m, 2.8H) 6.92-7.11 (m, 1.5H) 7.21(d, J=2.75 Hz, 1.0H) 7.27-7.49 (m, 7.0H) 7.53 (d, J=7.93 Hz, 0.6H) 7.87(dd, J=8.55, 4.88 Hz, 1.0H) 7.91-8.03 (m, 0.9H) 8.83 (s, 0.2H) 9.67 (s,0.3H).

Example 17

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-hydroxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(+/−)-

(+1-) Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-11-(phenylmethoxy)-(189mg, 0.26 mMol) was dissolved in a mixture of 5 ml methanol and 2 ml ofinhibitor free THF using heat. Upon cooling some material precipitatedout. Aqueous 1N hydrochloric acid (0.3 ml, 0.3 mMol) was added to aiddissolution. The reaction was placed under a nitrogen atmosphere priorto the addition of 20% palladium hydroxide on carbon (46 mg). Thereaction was run under hydrogen at atmospheric pressure (balloon) androom temperature for 6.75 hours. The reaction was filtered through aplug of ceilite. The volatiles of the filtrate were removed in vacuuo toyield 161 mg (92%) product as a pale yellow solid. 1H NMR (500 MHz,DMSO-D6) δ ppm 0.01 (t, J=5.34 Hz, 0.3H) 0.39 (s, 0.3H) 1.08-1.60 (m,6.6H) 1.62-1.83 (m, 2.9H) 1.82-2.20 (m, 6.3H) 2.58-2.84 (m, 4.9H)2.84-2.96 (m, 6.9H) 3.07-3.19 (m, 1.0H) 3.20-3.29 (m, 1.6H) 3.34 (s,10.0H, H₂O) 3.42 (s, 0.9H) 3.58 (d, J=14.65 Hz, 0.8H) 4.13 (d, J=14.95Hz, 0.4H) 4.31-4.62 (m, 0.8H) 4.91 (d, J=14.95 Hz, 0.3H) 4.98-5.21 (m,0.7H) 6.85 (t, J=8.55 Hz, 1.1H) 6.99 (s, 1.0H) 7.09-7.25 (m, 1.0H) 7.62(d, J=20.14 Hz, 1.0H) 7.72-7.91 (m, 1.0H) 7.92-8.29 (m, 0.9H) 9.92 (s,1.0H) 10.16 (d, J=56.15 Hz, 0.8H) 11.63 (d, J=10.68 Hz, 0.9H).

Example 18

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-N-[(methylamino)sulfonyl]-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(−)-

A solution of cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid,8-cyclohexyl-5-[[[(methylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(158mg, 0.29 mmol), 3-methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride(59 mg, 0.29 mmol), diisopropyl ethyl amine (0.15 mL), and TBTU (112 mg,0.35 mmol) in DMF (1.5 mL) was stirred for 1 hr at 22° C. and purifiedby prep HPLC to afford the title compound as a pale yellow solid (150mg, 80.1%). ESI-MS m/e 646 (MH), 1H NMR (500 MHz, MeOD) δ ppm 0.93-2.08(m, 16H) 2.49-2.53 (m, 1H) 2.55 (s, 3H) 2.60-2.93 (m, 4H) 3.15 (s, 3H)3.24 (m, 2H) 3.73 (s, 3H) 3.88-4.18 (m, 1H) 4.41-4.56 (m, 1H) 4.86-5.03(m, 1H) 6.86 (d, J=8.24 Hz, 1H) 6.97-7.06 (m, 1H) 7.09-7.20 (m, 1H)7.37-7.49 (m, 1H) 7.73 (d, J=8.24 Hz, 1H) 7.77-7.94 (m, 1H).

Example 19

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-N-[[(phenylmethyl)amino]sulfonyl]-,(+/−)-

(+/−)8-cyclohexyl-N-((benzylamino)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-11-(methyloxy)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamidewas prepared in a similar fashion to that described for the synthesis of(−)8-cyclohexyl-N-((methylamino)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-11-(methyloxy)-1,1a,2,12b-tetrahydrocycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamidestarting from (+/−)Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(benzylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-(methoxy)-12-(methoxy)-,methyl ester. ESI-MS m/e 722 (MH⁺), 1H NMR (500 MHz, MeOD) δ ppm1.14-2.20 (m, 16H) 2.56-3.08 (m, 7H) 3.39-3.72 (m, 3H) 3.89-3.96 (m, 3H)4.21-4.37 (m, 3H) 4.60-4.74 (m, 1H) 5.11-5.22 (m, 1H) 7.06 (dd, J=8.55,2.44 Hz, 1H) 7.17-7.24 (m, 2H) 7.28 (t, J=7.63 Hz, 2H) 7.33-7.43 (m, 3H)7.45-7.56 (m, 1H) 7.86-8.00 (m, 2H).

Example 20

Cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide,N-(aminosulfonyl)-8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-,(+/−)-

10% Palladium on carbon (40 mg, 0.038 mmol) was added to a solution of(+/−)8-cyclohexyl-N-((benzylamino)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-11-(methyloxy)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(+/−)(20 mg, 0.028 mmol) in EtOH (10 mL) and the reaction mixture wassequentially subjected to a vacuum and then flushed with nitrogen threetimes before being placed under a hydrogen atmosphere (1 atm). Thereaction mixture was stirred at rt for two days before being filteredthrough a pad of celite and concentrated. The residue was purified bypreparative HPLC (Acetonitrile/H₂O with a TFA buffer) to yield the titlecompound as a white film. ESI-MS m/e 632 (MH⁺), 1H NMR (500 MHz, MeOD) δppm 1.13-2.23 (m, 16H) 2.48-3.11 (m, 9H) 3.54-3.75 (m, 1H) 3.86-3.97 (m,3H) 4.15-4.37 (m, 1H) 4.62 (s, 1H) 5.19 (s, 1H) 7.05 (s, 1H) 7.16-7.24(m, 1H) 7.31-7.39 (m, 1H) 7.55-7.67 (m, 1H) 7.88-7.97 (m, 1H) 7.99-8.12(m, 1H).

Examples 20-31 were analyzed by the following LC/MS method AnalysisConditions: Column: PHENOMENNEX-LUNA 3.0×50 mm S10; Mobile Phase: (A)10:90 methanol-water; (B) 90:10 methanol-water; Buffer: 0.1% TFA;Gradient Range: 0-100% B; Gradient Time: 2 min; Flow Rate: 4 mL/min;Analysis Time: 3 min; Detection: Detector 1:UV at 220 nm; Detector 2:MS(ESI+).

Example 21

(+/−)-8-Cyclohexyl-5-(morpholinosulfonylcarbamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a-carboxylicacid

The product was purified by prep HPLC and isolated as a beige solid.LC/MS: Retention time: 1.968 min; m/e 460 (MH⁺). ¹H NMR (400 MHz,CDCl₃): The compound was observed to exist as inter-converting rotamers.

Example 22

(+/−)-8-Cyclohexyl-5-(4-methylpiperazin-1-ylsulfonylcarbamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a-carboxylicacid

The product was purified by prep HPLC and isolated in mono TFA salt formas a beige solid. LC/MS: Retention time: 1.687 min; m/e 607 (MH⁺). ¹HNMR (400 MHz, CDCl₃): The compound was observed to exist asinter-converting rotamers.

Example 23

(+/−)-8-Cyclohexyl-N-4-(morpholinosulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by prep HPLC and isolated as the TFA salt.LC/MS: Retention time: 1.770 min; m/e 702 (MH⁺). The compound wasobserved to exist as inter-converting rotamers by 1H NMR (500 MHz,CHLOROFORM-D): δ ppm 1.14-1.59 (m, 7H), 1.69-1.88 (m, 3H), 1.87-2.15 (m,6H,), 2.49-2.66 (m, 1H), 2.80-3.02 (m, 3H), 3.05-3.32 (m, 1H), 3.41-3.55(m, 5H), 3.58-3.68 (m, J=15.56 Hz, 1H), 3.70-3.81 (m, 4H), 3.83-3.93 (m,3H), 3.94-4.14 (m, 1H), 4.43-4.71 (m, 3H), 4.75-4.87 (m, 1H), 5.18 (s,1H), 6.90-7.02 (m, 1H), 7.07-7.15 (m, J=2.75 Hz, 1H), 7.27-7.36 (m,J=9.16, 9.16 Hz, 1H), 7.37-7.60 (m, 1H), 7.83-7.95 (m, J=8.39, 8.39 Hz,1H), 8.03 (s, 1H), 9.47 (s, 1H).

Example 24

(+/−)-8-Cyclohexyl-N-(pyrrolidin-1-ylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by prep HPLC and isolated as the TFA salt.LC/MS: Retention time: 2.873 min; m/e 686 (MH⁺). The compound wasobserved to exist as inter-converting rotamers by ¹H NMR (400 MHz,CHLOROFORM-D): δ ppm 1.12-1.30 (m, 3H), 1.29-1.45 (m, 3H), 1.45-1.60 (m,2H), 1.71-1.86 (m, 3H), 1.86-1.98 (m, J=6.17, 6.17 Hz, 6H), 1.97-2.12(m, J=23.42 Hz, 3H), 2.12-2.32 (m, 1H), 2.56-2.72 (m, 1H), 2.80-2.88 (m,J=4.78 Hz, 1H), 2.88-3.02 (m, 2H), 3.07-3.23 (m, 1H), 3.45-3.52 (m, 1H),3.51-3.60 (m, 4H), 3.60-3.74 (m, 2H), 3.85-3.93 (m, 3H), 4.02-4.18 (m,1H), 4.50-4.64 (m, 1H), 4.78-4.92 (m, 1H), 5.10-5.26 (m, 1H), 6.90-7.02(m, 1H), 7.07-7.16 (m, J=2.52 Hz, 1H), 7.26-7.34 (m, J=9.19, 9.19 Hz,1H), 7.48-7.64 (m, 1H), 7.82-7.97 (m, J=9.19, 9.19 Hz, 1H), 8.08-8.27(m, 1H), 9.52 (s, 1H).

Example 25

(+/−)-8-Cyclohexyl-N-(piperidin-1-ylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by prep HPLC and isolated as the TFA salt.LC/MS: Retention time: 1.882 min; m/e 700 (MH⁺). The compound wasobserved to exist as inter-converting rotamers by 1H NMR (400 MHz,CHLOROFORM-D): ppm 1.17-1.30 (m, 2H), 1.30-1.46 (m, J=14.23, 6.92 Hz,4H), 1.47-1.61 (m, J=11.33 Hz, 4H), 1.61-1.72 (m, J=4.03 Hz, 4H),1.71-1.86 (m, 3H), 1.86-2.11 (m, J=10.32 Hz, 6H), 2.21-2.38 (m, 1H),2.51-2.68 (m, 1H), 2.77-3.02 (m, 3H), 3.33-3.47 (m, 4H), 3.47-3.52 (m,1H), 3.58-3.73 (m, 2H), 3.86-3.93 (m, 3H), 3.93-4.13 (m, 1H), 4.57-4.77(m, 2H), 5.06-5.23 (m, 1H), 6.91-7.02 (m, 1H), 7.06-7.16 (m, J=2.52 Hz,1H), 7.26-7.33 (m, 1H), 7.37-7.56 (m, 1H), 7.82-7.94 (m, 1H), 7.98-8.12(m, 1H), 9.03 (s, 1H).

Example 26

(+/−)-8-Cyclohexyl-N-((2S,6R)-2,6-dimethylmorpholinosulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by prep HPLC and isolated as the TFA salt.LC/MS: Retention time: 2.911 min; m/e 730 (MH⁺). The compound wasobserved to exist as inter-converting rotamers by 1H NMR (400 MHz,CHLOROFORM-D): δ ppm 1.13-1.23 (m, 5H), 1.22-1.31 (m, J=5.29 Hz, 1H),1.31-1.47 (m, J=7.30, 7.30 Hz, 3H), 1.47-1.62 (m, 1H), 1.74-1.91 (m,J=20.90 Hz, 1H), 1.91-2.10 (m, 2H), 2.70-2.92 (m, 4H), 3.02-3.12 (m,1H), 3.18-3.39 (m, 6H), 3.44-3.52 (m, 3H), 3.58-3.79 (m, 8H), 3.90 (s,3H), 3.92-4.01 (m, 1H), 4.00-4.11 (m, 1H), 4.30-4.47 (m, 1H), 4.80-4.93(m, 1H), 5.09-5.23 (m, 1H), 6.92-7.02 (m, 2H), 7.08-7.14 (m, J=2.52 Hz,1H), 7.29 (d, J=8.31 Hz, 1H), 7.85-7.93 (m, 1H), 7.94-8.02 (m, 1H), 8.85(s, 1H).

Example 27

(+/−)-8-Cyclohexyl-N-4-(4-methylpiperazin-1-ylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by prep HPLC and isolated as bis-TFA salt.LC/MS: Retention time: 1.563 min; m/e 715 (MH⁺). The compound wasobserved to exist as inter-converting rotamers by ¹H NMR (500 MHz,CHLOROFORM-D): δ ppm 0.23-0.33 (m, 1H), 1.14-1.30 (m, 2H), 1.28-1.46 (m,3H), 1.45-1.61 (m, 1H), 1.63-1.86 (m, 3H), 1.85-2.09 (m, 5H), 2.50-2.66(m, 1H), 2.77-2.90 (m, 4H), 2.88-3.17 (m, 4H), 3.44-3.54 (m, 2H),3.52-3.75 (m, 5H), 3.84-3.94 (m, 3H), 3.95-4.19 (m, 4H), 4.31-4.52 (m,1H), 4.55-4.70 (m, 1H), 4.73-4.87 (m, 1H), 5.00-5.23 (m, 1H), 6.89-7.05(m, 2H), 7.05-7.15 (m, 1H), 7.25-7.32 (m, 1H), 7.45-7.64 (m, 1H),7.78-7.91 (m, 1H), 7.95-8.13 (m, 1H).

Example 28

(+/−)-8-Cyclohexyl-N-(isopropylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by prep HPLC and isolated in mono TFA salt formas a beige solid. LC/MS: Retention time: 1.818 min; m/e 659 (MH⁺). Thetitle compound was observed to exist as inter-converting rotamers by 1HNMR (400 MHz, CHLOROFORM-D): ppm 1.11-1.29 (m, 2H), 1.28-1.66 (m, 8H),1.67-1.87 (m, 3H), 1.86-2.11 (m, 5H), 2.12-2.42 (m, 2H), 2.43-2.72 (m,2H), 2.72-3.04 (m, 4H), 3.05-3.30 (m, J=7.55, 4.28 Hz, 2H), 3.31-3.57(m, 2H), 3.57-3.78 (m, J=18.63 Hz, 2H), 3.85-3.93 (m, 3H), 3.96-4.15 (m,2H), 4.37-4.76 (m, J=71.51 Hz, 1H), 5.04-5.25 (m, 1H), 6.86-7.02 (m,1H), 7.07-7.16 (m, J=2.52 Hz, 1H), 7.26-7.36 (m, J=8.31, 8.31 Hz, 1H),7.44-7.69 (m, 1H), 7.90 (d, J=8.56 Hz, 1H), 8.00-8.29 (m, J=48.09 Hz,1H), 9.33 (s, 1H).

Example 29

(+/−)-8-Cyclohexyl-N—(N,N-dimethylsulfamoyl)-1,1a,2,12b-tetrahydro-11-difluoromethoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was prepared by difluoromethylation (ClCHF₂, 1N NaOH,acetone-isopropanol, rt) of corresponding phenolic derivative and waspurified by prep HPLC and isolated in mono TFA salt form as a beigesolid. LC/MS: Retention time: 1.798 min; m/e 696 (MH⁺). The titlecompound was observed to exist as inter-converting rotamers by 1H NMR(500 MHz, CHLOROFORM-D): δ ppm 0.25-0.81 (m, 3H), 0.81-1.33 (m, 6H),1.29-1.64 (m, 4H), 1.78 (s, 2H), 1.85-2.17 (m, J=4.58 Hz, 4H), 2.36-2.59(m, 2H), 2.79 (t, J=11.90 Hz, 2H), 2.84-2.93 (m, 1H), 2.97-3.10 (m, 5H),3.08-3.23 (m, 1H), 3.45 (s, 1H), 4.40 (s, 1H), 5.07 (s, 1H), 6.44-6.66(m, 1H), 6.73-6.86 (m, J=14.34 Hz, 1H), 7.17 (d, J=1.83 Hz, 1H), 7.28(dd, J=8.55, 2.44 Hz, 1H), 7.42-7.60 (m, 2H), 7.92 (d, J=8.55 Hz, 1H),8.09 (s, 1H), 8.91 (s, 1H).

Example 30

(+/−)-8-Cyclohexyl-N—(N,N-dimethylsulfamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-1amethyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-N-methyl-5-carboxamide

The product was prepared by N-methylation of(+/−)-8-cyclohexyl-N—(N,N-dimethylsulfamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamideunder Mitsonobu conditions (Ph₃P, DEAD, MeOH-THF, 0-23° C.), and waspurified by prep HPLC and isolated in mono TFA salt form as a beigesolid. LC/MS: Retention time: 1.828 min; m/e 674 (MH⁺). The titlecompound was observed to exist as inter-converting rotamers by 1H NMR(400 MHz, CHLOROFORM-D): δ ppm 1.12-1.62 (m, 6H), 1.65-2.32 (m, 8H),2.46 (d, J=5.29 Hz, 2H), 2.69-2.91 (m, 3H), 2.90-2.99 (m, 7H), 2.96-3.19(m, 2H), 3.25-3.34 (m, 3H), 3.33-3.43 (m, 1H), 3.49 (s, 1H), 3.63 (d,J=15.36 Hz, 1H), 3.67-3.84 (m, J=1.51 Hz, 1H), 3.89 (s, 3H), 3.93-4.20(m, 1H), 4.44-4.67 (m, 1H), 5.09-5.27 (m, 1H), 6.92-7.02 (m, J=8.69,2.64 Hz, 1H), 7.06-7.14 (m, J=2.52 Hz, 1H), 7.26-7.33 (m, 2H), 7.64 (s,1H), 7.89 (d, J=8.31 Hz, 1H).

Example 31

(+/−)-8-Cyclohexyl-N-(N-cyclopropylsulfamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-N-methyl-5-carboxamide

The product was purified by prep HPLC and isolated in mono TFA salt formas a beige solid. LC/MS: Retention time: 2.751 min; m/e 672 (MH⁺). Thetitle compound was observed to exist as inter-converting rotamers by 1HNMR (400 MHz, CHLOROFORM-D): δ ppm 0.55-0.96 (m, 3H), 1.05-1.59 (m, 6H),1.60-2.19 (m, 8H), 2.22-2.45 (m, 2H), 2.44-2.81 (m, 6H), 2.81-3.09 (m,4H), 3.36-3.52 (m, J=25.68 Hz, 1H), 3.59-3.80 (m, 2H), 3.82-3.94 (m,3H), 3.97-4.19 (m, 1H), 5.14-5.29 (m, 1H), 5.99 (s, 1H), 6.90-7.02 (m,J=8.44, 2.90 Hz, 1H), 7.06-7.14 (m, J=2.52 Hz, 1H), 7.26-7.35 (m, 1H),7.53-7.71 (m, 1H), 7.93 (d, J=8.56 Hz, 1H), 8.23 (s, 1H), 9.95 (s, 1H).

Examples 32-36 were analyzed by the following LC/MS method: Start % B:0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4ml/min; Wavelenth: 220; Solvent A: 10% MeOH/90% H₂O/0.1% TrifluoroaceticAcid; Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column:XBridge 4.6×50 mm S5.

Example 32

(+/−)-8-cyclohexyl-N-(methylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

A mixture of indole carboxylic acid-cyclopropylester (1.3 g, 2.83 mmol)and CDI (0.64 g, 3.97 mmol) in THF (20 mL) was heated at 50° C. for 0.5h, cooled down and added methylsulfonamide (0.4 g, 4.2 mmol) and DBU(0.264 mL, 1.77 mmol). The mixture was stirred for 20 h and diluted withEtOAc, washed with cold 1N HCl (2×), brine, dried (MgSO4), removed thesolvent and purified by flash (Biotage 40 M) to afford the compound 1-2(1.28 g, 85%) as a pale yellow solid. LC-MS retention time: 3.51; MS m/z537 (M+H). The sulfonamide was observed to exist as inter-convertingrotamers. The major isomer: ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm1.11-2.17 (m, 12H), 2.84-2.98 (m, 2H), 3.43 (d, J=14.86 Hz, 1H), 3.49(s, 3H), 3.55 (s, 3H), 3.89 (s, 3H), 5.40 (d, J=15.11 Hz, 1H), 6.91-6.96(m, 1H), 7.13 (d, J=2.52 Hz, 1H), 7.22-7.27 (m, 1H), 7.39 (dd, J=8.31,1.51 Hz, 1H), 7.85 (d, J=8.81 Hz, 1H), 8.23 (d, J=1.26 Hz, 1H), 8.75 (s,1H).

To a solution of the sulfonamide-ester (1.28 g, 2.4 mmol) in THF (5 mL)and MeOH (5 mL) was added NaOH (1N, 12 mL, 12 mmol). After being stirredat room temperature for 3 h, the mixture was diluted with EtOAc, washedwith cold 1N HCl, brine, dried (MgSO4), and removed the solvent in vacuoto afford the acid as a beige solid (1.20 g, 96%). LC-MS retention time:3.46; MS m/z 523 (M+H). Compound 1-2 was observed to exist asinter-converting rotamers (˜1/1) ¹H NMR (400 MHz, CHLOROFORM-D).

To a mixture of the acid (0.060 g, 0.11 mmol) and3-methyl-3,8-diazabicyclo[3.2.1]octane bishydrochloric acid salt (0.034g, 0.17 mmol) in DMC (1.5 mL) was added Et₃N (0.096 mL, 0.69 mmol) andHBTU (0.065 g, 0.17 mmol). The mixture was stirred at room temperaturefor 0.5 h, diluted with MeOH, removed the solvent. The residue wasdissolved in methanol, filtered, and purified by prep-HPLC to afford ATFA salt of the product (0.0378 g, 82%) in TFA salt. LC-MS retentiontime: 2.96; MS m/z 631 (M+H). The product was observed to exist asinter-converting rotamers ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.04-1.61(m, 8H), 1.68-2.38 (m, 10H), 2.48-3.03 (m, 6H), 3.09-3.20 (m, 1H) 3.30,−3.78 (m, 2H), 3.41 (s, 3H), 3.88 (s, 3H), 4.05 (d, J=14.10 Hz, 1H),5.06-5.28 (m, 1H), 6.97 (dd, J=8.81, 2.27 Hz, 1H), 7.11 (d, J=2.27 Hz,1H), 7.24-7.34 (m, 1H), 7.54-7.73 (m, 1H), 7.82-7.94 (m, J=7.18, 5.41Hz, 1H), 8.17 (s, 1H).

Example 33

(+/−)-8-cyclohexyl-N-(ethylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

In a manner similar to that above, the product was prepared: sulfonamide(0.47 g, 44%); LC-MS retention time: 3.54; MS m/z 551 (M+H); acid (0.43g, 94%); LC-MS retention time: 3.49; MS m/z 537 (M+H). A TFA salt of theproduct was prepared (0.0378 g, 71%). LC-MS retention time: 3.028 MS m/z645 (M+H). The product was observed to exist as inter-convertingrotamers, the major isomer: ¹H NMR H NMR (500 MHz, ppm 1.12-2.37 (m,19H), 2.51-2.66 (m, 1H), 2.69-3.03 (m, 4H), 3.08-3.22 (m, 1H), 3.21-3.83(m, 8H), 3.90 (s, 3H), 5.11-5.28 (m, 1H), 6.87-6.95 (m, 1H), 6.97-7.00(m, 1H), 7.12 (d, J=2.14 Hz, 1H), 7.30 (d, J=8.85 Hz, 1H), 7.88-7.96 (m,1H), 8.08 (s, 1H).

Example 34

(+/−)-8-Cyclohexyl-N-(azetidin-1-ylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

In a manner similar to that above, the product was prepared: sulfonamide(0.96 g, 59%); LC-MS retention time: 3.58; MS m/z 578 (M+H). Thecompound was observed to exist as inter-converting rotamers (3/4). Themajor isomer: ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.16-1.59 (m, 4H),1.72 (dd, J=9.44, 4.15 Hz, 3H), 1.88-2.12 (m, 4H), 2.24-2.36 (m, 2H),2.75-2.97 (m, 2H), 3.44 (d, J=14.86 Hz, 1H), 3.56 (s, 3H), 3.89 (s, 3H),4.09 (d, 1H), 4.24-4.37 (m, 4H), 5.41 (d, J=14.86 Hz, 1H), 6.92-6.96 (m,1H), 7.13 (d, J=2.01 Hz, 1H), 7.24-7.30 (m, 1H), 7.39 (dd, J=8.31, 1.51Hz, 1H), 7.84-7.88 (m, 1H), 8.24 (d, J=1.51 Hz, 1H); acid (0.93 g,100%); LC-MS retention time: 3.51; MS m/z 564 (M+H). Compound wasobserved to exist as inter-converting rotamers (˜3/4). The major isomer:¹H NMR (400 MHz, ppm 0.34-0.42 (m, 1H), 1.15-2.10 (m, 11H), 2.22-2.38(m, 2H), 2.65-2.78 (m, 1H), 2.84-2.94 (m, J=3.02 Hz, 1H), 3.84 (s, 3H),4.03 (d, J=15.11 Hz, 1H), 4.21-4.43 (m, 4H), 5.34 (d, J=14.86 Hz, 1H),6.87 (dd, J=8.56, 2.77 Hz, 1H), 6.98 (d, J=2.52 Hz, 1H), 7.21 (d, J=8.31Hz, 1H), 7.69-7.75 (m, 1H), 7.86-7.90 (m, 1H), 8.13 (s, 1H). A TFA saltof the product was prepared: LC-MS retention time: 3.51; MS m/z 672(M+H). The title compound was observed to exist as inter-convertingrotamers in ¹H NMR (400 MHz, CHLOROFORM-D): ¹H NMR (400 MHz, ppm1.02-1.63 (m, 8H), 1.72-2.36 (m, 10H), 2.47-3.23 (m, 6H), 3.45 (d,J=29.46 Hz, 2H), 3.59-3.75 (m, 2H), 3.89 (s, 3H), 4.12-4.38 (m, 4H),4.38-4.98 (m, 2H), 5.12-5.30 (m, 1H), 6.90-7.03 (m, 2H), 7.12 (d, J=2.52Hz, 1H), 7.27-7.35 (m, J=9.06, 9.06 Hz, 1H), 7.59-7.75 (m, 1H),7.84-7.96 (m, 1H).

Example 35

(+/−)-8-Cyclohexyl-N-(N-ethyl-N-methylaminosulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Prepared from the acid in similar method as described above. Sulfonamide(0.109 g, 67%). LC-MS retention time: 3.60; MS m/z 580 (M+H). Compoundwas observed to exist as inter-converting rotamers (˜5/4). The majorisomer: ¹H NMR (400 MHz, ppm 1.16-2.09 (m, 14H), 2.73-2.93 (m, 2H), 3.07(s, 3H), 3.31-3.52 (m, 3H), 3.76 (s, 3H), 3.88 (s, 3H), 4.05-4.10 (m,1H), 5.40 (d, J=15.11 Hz, 1H), 6.88-6.93 (m, 1H), 7.13 (d, J=2.27 Hz,1H), 7.22-7.29 (m, 1H), 7.33-7.42 (m, 1H), 7.82-7.86 (m, 1H), 8.19 (d,J=1.51 Hz, 1H). Acid (0.108 g, 100%). LC-MS retention time: 3.55; MS m/z566 (M+H). A TFA salt of the product was prepared (0.0437 g, 54%). LC-MSretention time: 3.10; MS m/z 674 (M+H). 1H NMR (500 MHz, ppm 1.14-1.62(m, 6H), 1.22 (t, J=7.17 Hz, 3H), 1.69-2.21 (m, 10H), 2.25-3.31 (m,11H), 3.02 (s, 3H), 3.43 (q, J=7.02 Hz, 2H), 3.55-3.80 (m, 1H), 3.89 (s,3H), 5.08-5.29 (m, 1H), 6.93-7.00 (m, 1H), 7.11 (d, J=2.44 Hz, 1H),7.28-7.31 (m, 1H), 7.39-7.56 (m, 1H), 7.85-7.91 (m, 1H), 8.04 (s, 1H).

Example 36

(+/−)-8-Cyclohexyl-N—(N-ethyl-N-methylaminosulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Prepared from the acid in similar method as described above. Sulfonamide(0.127 g, 67%); LC-MS retention time: 3.64; MS m/z 594 (M+H). Compoundwas observed to exist as inter-converting rotamers: ¹H NMR (400 MHz, ppm1.11-2.13 (m, 18H), 2.64 (dd, J=10.07, 6.80 Hz, 1H), 2.84-2.96 (m, 1H),3.34-3.67 (m, 4H), 3.75 (s, 3H), 3.88 (s, 3H), 4.03-4.10 (m, 1H), 5.40(d, J=15.36 Hz, 1H), 6.90-6.95 (m, 1H), 7.13 (d, J=2.01 Hz, 1H),7.21-7.29 (m, 1H), 7.33-7.39 (m, 1H), 7.83 (d, J=8.06 Hz, 1H), 8.20 (d,J=1.26 Hz, 1H). Acid: (0.126 g, 100%). LC-MS retention time: 3.57; MSm/z 580 (M+H). A TFA salt of the product was prepared (0.431 g, 52%).LC-MS retention time: 3.18; MS m/z 688 (M+H). ¹H NMR (400 MHz,CHLOROFORM-D) d ppm 1.13-1.55 (m, 6H), 1.21 (t, J=7.18 Hz, 6H),2.31-3.55 (m, 11H), 2.41-3.29 (m, 10H), 3.49 (q, J=7.05 Hz, 4H),3.59-3.67 (m, 1H), 3.89 (s, 3H), 5.02-5.29 (m, 1H), 6.97 (dd, J=8.81,2.27 Hz, 1H), 7.10 (d, J=2.52 Hz, 1H), 7.28 (d, J=8.56 Hz, 1H),7.36-7.49 (m, 1H), 7.83-7.91 (m, 1H), 7.95-8.06 (m, 1H).

Example 37

Neat 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (0.0535 g, 0.167 mmol) was added to stirred mixture ofCompound I-4 (0.0774 g, 0.128 mmol),3-methyl-3,8-diazabicyclo[3.2.1]octane, 2HCl (0.026.4 g, 0.128 mmol) andTEA (0.071 ml, 0.512 mmol) in DCM (2 ml) under nitrogen. The mixture wasstirred at rt for 1 h and quenched with MeOH (0.5 ml) and thenevaporated to dryness and purified by reverse-phase HPLC to affordisolated in mono TFA salt form of the product (0.0613 g, 60%)) as abeige solid. LC/MS: m/e 686 (MH⁺). LC/MS method: Start % B: 0, Final %B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 ml/min;Wavelength: 220; Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid;Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column: XBridge4.6×50 mm S5.

Example 38

The TFA salt of the amide (0.0465 g 56%) was made from the acid (0.060g, 0.104 mmol) and amine using HBTU and TEA in methylene chloride. LC-MSretention time: 3.146 min; MS m/z (M+H) 688. LC/MS method: Start % B: 0,Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4ml/min; Wavelenth: 220; Solvent A: 10% MeOH/90% H₂O/0.1% TrifluoroaceticAcid; Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column:XBridge 4.6×50 mm S5. 1H NMR existed rotomers, The major form: 1H NMR(400 MHz, CHLOROFORM-d) o ppm 1.14-1.18 (m, 6H) 1.19-2.12 (m, 16H)2.19-3.77 (m, 9H) 2.95 (s, 3H) 3.89 (s, 3H) 3.95-5.02 (m, 4H) 5.03-5.24(m, 1H) 6.97 (dd, J=8.81, 2.77 Hz, 1H) 7.11 (d, J=2.52 Hz, 1H) 7.28 (d,J=8.56 Hz, 1H) 7.40-7.64 (m, 1H) 7.88 (d, J=8.31 Hz, 1H) 8.07 (br. s.,1H).

Additional Compounds

Additional compounds can be made using the following routes.

To a 250 mL RBF equipped with a stir bar was added bromocyclobutane(3.49 mL, 37.0 mmol) and 70 mL of diethyl ether. The flask was cooled to−78° C. (acetone/dry ice bath). To this solution was then added, viasyringe, 2.0 eq. of a 1.7M solution of tert-butyllithium (43.6 mL, 74.1mmol). The mixture was stirred for 60 minutes, then cannulated into a500 mL flask containing sulfuryl chloride (6.00 mL, 74.1 mmol) in 30 mLof diethylether at −78° C. The suspension was warmed to room temperatureovernight. The white mixture was diluted with 40 mL of diethylether,filtered and set aside. A 3 necked 500 mL RBF equipped with a stir barand dry THF (10 mL) was cooled to −65° C. with the aid of a dryice/isopropanol bath and gaseous ammonia was slowly sparged into theflask. Previously synthesized cyclobutanesulfonyl chloride (5.2 g, 33.6mmol) was then dripped in via syringe (crude mixture in ˜200 mL ofether/THF). Sparging of ammonia gas was continued for an additional 5minutes. The mixture was kept at −65° C. for 4 hours then allowed toslowly warm to room temperature. The reaction mixture was filtered andwashed with 100 mL of THF. The solvent was evaporated to give 2.1 g ofthe desired sulfonamide (46% yield) as a pale yellow oily solid. ¹H NMR(500 MHz, DMSO-D6): δ ppm 1.81-1.89 (m, 2H), 2.16-2.22 (m, 2H),2.23-2.31 (m, 2H), 3.66-3.74 (m, 1H), 6.68 (s, 2H).

¹H NMR (500 MHz, DMSO-D6): δ ppm 0.94 (m, 3H), 1.20 (m, 3H), 1.30-1.45(m, 1H), 1.90 (m, 1H), 2.76 (m, 1H), 6.59 (s, 2H).

¹H NMR (500 MHz, DMSO-D6): δ ppm 1.02 (d, J=6.95 Hz, 6H), 2.11 (m, 1H),2.86 (d, J=6.22 Hz, 2H), 6.71 (s, 2H).

¹H NMR (500 MHz, DMSO-D6): δ ppm 1.51-1.66 (m, 4H), 1.86 (m, 4H), 3.37(m, 1H), 6.65 (s, 2H).

¹H NMR (500 MHz, DMSO-D6): δ ppm 4.24 (m, 2H), 7.46 (s, 2H).

¹H NMR (500 MHz, DMSO-D6): δ ppm 2.70 (m, 2H), 3.20 (m, 2H), 7.01 (s,2H).

¹H NMR (500 MHz, DMSO-D6): δ ppm 1.07-1.17 (m, 1H), 1.22-1.38 (m, 4H),1.62 (m, 1H), 1.78 (m, 2H), 2.05 (m, 2H), 2.68-2.77 (m, 1H), 6.57 (s,2H).

¹H NMR (300 MHz, DMSO-D6): δ ppm 1.22 (d, J=6.59 Hz, 6H), 3.00 (m, 1H),6.59 (s, 2H).

Methyl10-((sec-butylsulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate

In a 100 mL round-bottomed flask (RBF) was added carboxylic acid 1 (575mg, 1.291 mmol) and 1,1′-carbonyldiimidazole (460 mg, 2.84 mmol) in THF(15 mL) to give a yellow solution. The mixture was stirred at roomtemperature under nitrogen for 1 hour then heated to 70° C., in an oilbath, for 90 minutes. The mixture was cooled and sec-butyl sulfonamide(921 mg, 6.71 mmol) in 4 mL of THF was added along with neat DBU (0.389mL, 2.58 mmol). The RBF was returned to the oil bath and heatedovernight at 70° C. The reaction mixture was transferred to a separatoryfunnel, diluted with 100 mL of DCM, washed ×3 with 100 mL of 0.5 M HCl,then with 100 mL of H₂O, and finally saturated NaCl. The organic mixturewas dried over MgSO₄, filtered and concentrated to give 713 mgs of thedesired acylsulfonamide 2 as a yellow solid (96% yield) which was placedunder vacuum overnight. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Phenomenex-Luna 10 g, C18, 4.6×30mm column, using a SPD-10AV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 5 ml/min., agradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B,a gradient time of 2 min., a hold time of 1 min., and an analysis timeof 3 min. where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acidand solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS datawas determined using a Micromass Platform for LC in electrospray mode.1H NMR (500 MHz, CD₃OD): 6 ppm 0.84-0.92 (m, 3H), 1.03 (t, J=7.32 Hz,3H), 1.23 (m, 1H), 1.28-1.44 (m, 7H), 1.58 (m, 1H), 1.72 (m, 2H), 1.85(m, 1H), 1.95-2.07 (m, 3H), 2.17 (m, 1H), 2.78 (m, 1H), 3.69 (m, 2H),3.83-3.91 (m, 3H), 7.02 (s, 1H), 7.11 (m, 1H), 7.47 (d, J=7.63 Hz, 1H),7.74 (m, 3H), 8.25 (s, 1H). LC/MS: m/z 565.22, Rf 2.192 min., 97.5%purity.

Methyl5-((sec-butylsulfonyl)carbamoyl)-8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate

To 63.1 mgs of 95% NaH in 5 mL of dry DMF in a 100 mL RBF was added 629mgs of trimethylsulfoxonium iodide at room temperature. The mixture wasstirred at room temperature under nitrogen for 30 minutes. A solution ofIntermediate 9 (in 7 mL of DMF) was added via syringe and the reactionwas stirred for 15-20 minutes. The reaction mixture was quickly cooledto 0° C. with an ice bath, 1 mL of 1 M HCl was added followed by 60 mLof ice water. The heterogeneous mixture was stirred for 30 minutes. Themixture was filtered and the yellow solid was washed with ice water. Thesolid was taken up in 2% methanol/DCM and was purified using a BiotageHorizon MPLC employing a 40+M column with a solvent gradient of 2%methanol/DCM to 10% methanol/DCM. 450 mgs (62% yield) of the compoundwas obtained as a yellow solid after solvent evaporation. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10 g, C18, 4.6×30 mm column, using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min., a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min., ahold time of 1 min., and an analysis time of 3 min. where solvent A was10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode. 1H NMR (300 MHz, CD₃OD): 6 ppm0.19 (m, 0.35H), 1.03-1.14 (m, 3H), 1.19-1.34 (m, 2.65H), 1.43 (m, 5H),1.55-1.66 (m, 2H), 1.74 (m, 2H), 1.89-1.94 (m, 2H), 1.99-2.14 (m, 3H),2.64-2.95 (m, 2H), 3.35 (d, J=15.00 Hz, 0.65H), 3.48 (m, 2H), 3.67-3.81(m, 2H), 3.85 (s, 3H), 3.90-3.98 (m, 0.35H), 5.17 (m, 0.35H), 5.36 (m,0.65H), 6.91-6.98 (m, 1H), 7.09 (m, 0.35H), 7.16 (m, 0.65H), 7.19-7.27(m, 1H), 7.52-7.65 (m, 1H), 7.83 (m, 1H), 8.09 (s, 0.35H), 8.29 (s,0.65H). LC/MS: m/z 579.31, Rf 2.167 min., 95.2% purity.

Methyl8-cyclohexyl-5-((cyclohexylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate

1H NMR (300 MHz, CD₃OD): δ ppm 0.23 (m, 0.35H), 1.14-1.53 (m, 10H),1.60-1.79 (m, 3H), 1.91 (m, 3H), 2.09 (m, 1.65H), 2.18 (m, 3H),2.81-2.98 (m, 3H), 3.41-3.46 (m, 0.65H), 3.50 (m, 2H), 3.71-3.79 (m,2H), 3.88 (s, 3H), 3.99-4.04 (m, 0.35H), 5.25 (m, 0.35H), 5.45 (m,0.65H), 6.97-7.02 (m, 1H), 7.13 (m, 0.35H), 7.21 (m, 0.65H), 7.26-7.32(m, 1H), 7.55-7.65 (m, 1H), 7.85-7.92 (m, 1H), 8.11 (s, 0.35H), 8.32 (s,0.65H). LC/MS: m/z 605.42, Rf 2.223 min., 99.2% purity.

Methyl8-cyclohexyl-5-((cyclopentylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate

1H NMR (300 MHz, CD₃OD): δ ppm 0.23 (m, 0.35H), 1.27 (m, 2.65H), 1.39(m, 2H), 1.60-1.79 (m, 7H), 1.91-2.19 (m, 8H), 2.67-2.97 (m, 2H), 3.47(m, 0.65H), 3.50 (m, 3H), 3.78-3.87 (m, 3H), 4.10 (m, 0.35H), 4.29 (m,1H), 5.22 (m, 0.35H), 5.43 (m, 0.65H), 6.98-7.02 (m, 1H), 7.14 (m,0.35H), 7.21 (m, 0.65H), 7.26-7.32 (m, 1H), 7.55-7.65 (m, 1H), 7.85-7.91(m, 1H), 8.10 (s, 0.35H), 8.32 (s, 0.65H). LC/MS: m/z 591.33, Rf 2.200min., 100% purity.

methyl8-cyclohexyl-11-methoxy-5-(((3,3,3-trifluoropropyl)sulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate

1H NMR (300 MHz, CD₃OD): ppm 0.19 (m, 0.35H), 1.25 (m, 1.65H), 1.41 (m,2H), 1.65 (m, 1H), 1.76 (m, 2H), 1.94 (m, 2H), 2.04 (m, 1H), 2.61-2.84(m, 6H), 2.88-2.96 (m, 1H), 3.35-3.40 (m, 0.65H), 3.48 (m, 2H), 3.80 (m,2H), 3.86 (m, 3H), 3.89-3.98 (m, 0.35H), 5.18 (m, 0.35H), 5.38 (m,0.65H), 6.96-7.01 (m, 1H), 7.13 (m, 0.35H), 7.20 (m, 0.65H), 7.24-7.30(m, 1H), 7.58-7.69 (m, 1H), 7.84-7.90 (m, 1H), 8.13 (s, 0.35H), 8.34 (s,0.65H). LC/MS: m/z 619.32, Rf 2.188 min., 99.5% purity.

methyl8-cyclohexyl-11-methoxy-5-(((2,2,2-trifluoroethyl)sulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate

1H NMR (300 MHz, CD₃OD): ppm 0.13 (m, 0.35H), 1.18 (m, 1.65H), 1.38 (m,2H), 1.57-1.62 (m, 2H), 1.73 (m, 2H), 1.87 (m, 2H), 1.96-2.05 (m, 1H),2.60-2.90 (m, 1.35H), 3.17-3.22 (m, 0.65H), 3.45 (m, 2H), 3.74 (m, 1H),3.84 (m, 2H), 4.04-4.10 (m, 3H), 4.38-4.53 (m, 2H), 5.06 (m, 0.35H),5.18 (m, 0.65H), 6.90-6.96 (m, 1H), 7.06 (m, 0.35H), 7.13 (m, 0.65H),7.16-7.22 (m, 1H), 7.63 (m, 0.65H), 7.70-7.80 (m, 1.35H), 8.14 (s,0.35H), 8.33 (s, 0.65H). LC/MS: m/z 605.29, Rf 2.178 min., 96.5% purity.

Methyl8-cyclohexyl-5-((isobutylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate

1H NMR (300 MHz, CD₃OD): δ ppm 0.17 (m, 0.35H), 1.09 (m, 6H), 1.22 (m,1.65H), 1.38 (m, 2H), 1.49-1.60 (m, 1H), 1.73 (m, 2H), 1.87 (m, 2H),1.96-2.05 (m, 2H), 2.15-2.39 (m, 1H), 2.61-2.87 (m, 2H), 2.96 (d, J=6.22Hz, 2H), 3.19 (m, 2H), 3.43 (m, 2H), 3.70 (m, 2H), 3.84 (m, 2H),5.06-5.11 (m, 1H), 6.90-6.95 (m, 1H), 7.05-7.11 (m, 1H), 7.16-7.23 (m,1H), 7.67-782 (m, 2H), 8.20 (s, 0.35H), 8.39 (s, 0.65H). LC/MS: m/z579.30, Rf 2.190 min., 96.2% purity.

General Procedure for the Transformation of Esters of Formula I toCorresponding Amides.

In a 100 mL round-bottomed flask was added 1 N sodium hydroxide (3 eq.,1.583 ml, 1.583 mmol) and bridged ester 1 (1 eq., 0.528 mmol) inmethanol (4.00 ml) and THF (4.00 ml) to give a yellow solution. Themixture was stirred for 3 hours at room temperature. 3 equivalents of 1N HCl was then added, the product diluted with ethyl acetate thenextracted, washed with brine and dried over MgSO₄. Filtration andsubsequent evaporation of volatiles gave the carboxylic acids 2 in nearquantitative yield. To a 0.10 mmol solution of carboxylic acid 2 in 1 mLof anhydrous N,N-Dimethylformamide (DMF) in a 2 dram vial equipped witha Teflon™ lined screw cap was added 0.3 mmol (3 eq.) of2-(1H-Benzotriazole-1-yl)-1,1,3,3,-Tetramethyluronium Tetrafluoroborate(TBTU) in 1.0 mL of anhydrous DMF followed by the addition of 0.2 mmol(2 eq.) of amine 3 in 1.0 mL of anhydrous DMF and 0.4 mmol of neatN,N-diisopropylethylamine. The reaction was shaken on a VWR Vortex-Genie2 Mixer overnight at room temperature. The reaction volumes were thenreduced in a Savant Speedvac and the crude products were taken up in 1.2mL of methanol and purified using a Shimadzu preparative HPLC employingmethanol/water and 0.1% trifluoroacetic acid buffer with a PhenomenexLuna, C18, 30 mm×100 mm, 10 gm column at a gradient of 40-100% B and aflow rate of 40 mL/min. over 10 minutes with a 5-10 minute hold, to givecarboxamides 4 as yellow amorphous solids (65%-70% yield).Post-purification LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Column I (Phenomenex 10 μm C18, 4.6×30 mm), Solvent system I(gradient of 0-100% B where B=90% HPLC grade methanol/0.1%trifluoroacetic acid/10% HPLC grade water), in 2 minutes with a 1 minutehold at a flow rate of 5 mL/minute.

8-Cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-N-((2,2,2-trifluoroethyl)sulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide

1H NMR (300 MHz, CD3OD): δ ppm 0.16 (m, 0.20H), 1.22-1.37 (m, 2.80H),1.45 (m, 3H), 1.62 (m, 1H), 1.78 (m, 3H), 1.92-2.21 (m, 5H), 2.52-2.69(m, 1H), 2.81 (m, 3H), 2.94 (m, 2H), 3.16 (m, 1H), 3.39 (m, 2H),3.51-3.65 (m, 2H), 3.85-3.92 (m, 3H), 4.15-4.37 (m, 1H), 4.66 (m, 3H),5.10 (m, 1H), 6.97-7.05 (m, 1H), 7.15 (d, J=1.83 Hz, 0.20H), 7.19 (d,J=1.83 Hz, 0.80H), 7.30 (d, J=8.42 Hz, 1H), 7.53-7.63 (m, 1H), 7.89 (d,J=8.42 Hz, 1H), 7.99-8.08 (m, 1H). LC/MS: m/z 699.35, Rf 1.810 min.,98.0% purity.

8-Cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-N-((3,3,3-trifluoropropyl)sulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide

1H NMR (300 MHz, CD₃OD): δ ppm 0.14 (m, 0.20H), 1.19-1.33 (m, 2.80H),1.42 (m, 3H) 1.60 (m, 1H), 1.76 (m, 3H), 2.00 (m, 5H), 2.54 (m, 1H),2.65 (m, 1H), 2.72-2.86 (m, 5H), 2.87-3.01 (m, 2H), 3.30-3.44 (m, 2H),3.49-3.63 (m, 2H), 3.78-3.89 (m, 5H), 4.17-4.29 (m, 1H), 4.64 (m, 1H),5.07 (m, 1H), 6.96-7.03 (m, 1H), 7.13 (d, J=2.56 Hz, 0.20H), 7.17 (d,J=2.56 Hz, 0.80H), 7.28 (d, J=8.42 Hz, 1H), 7.54 (d, J=8.42 Hz, 0.80H),7.59 (d, J=8.42 Hz, 0.20H), 7.83-7.90 (m, 1H), 7.97 (s, 0.80H), 8.07 (s,0.20H), LC/MS: m/z 713.36, Rf 1.822 min., 98.7% purity.

N-(sec-butylsulfonyl)-8-cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide

1H NMR (300 MHz, CD₃OD): δ ppm 0.17 (m, 0.20H), 1.08 (t, J=7.50 Hz, 3H),1.19-1.34 (m, 1.80H), 1.38-1.53 (m, 6H), 1.70 (m, 5H), 2.08 (m, 5H),2.40 (m, 1H), 2.67 (m, 1H), 2.82 (m, 3H), 2.94 (m, 3H), 3.27 (m, 1H),3.32-3.46 (m, 2H), 3.49-3.65 (m, 2H), 3.74 (m, 1H), 3.84-3.92 (m, 3H),4.21 (m, 1H), 4.65 (m, 1H), 5.10 (m, 1H), 6.97-7.05 (m, 1H), 7.14-7.20(m, 1H), 7.30 (m, 1H), 7.55 (m, 1H), 7.87-7.92 (m, 1H), 7.97-8.05 (m,1H). LC/MS: m/z 673.32, Rf 1.820 min., 98.2% purity.

Isomer-A and Isomer B were obtained from the SFC chiral separation of(1aR,12bS)—N-(sec-butylsulfonyl)-8-cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[c]indolo[2,1-a][2]benzazepine-5-carboxamidewhich was prepared from the chiral ethyl ester. SFC Separationconditions: Column: ChiralPak AD-H, 30×250 mm, 5 gm; Mobile Phase: 25%isopropyl alcohol/75% CO₂; Pressure: 100 bar; Temperature: 35° C.; FlowRate: 70 mL/min.; UV: 260 nm; Injection: 2 mL (˜5 mg/mL in 9:1 IPA:ACN);Collection: Isomer-A (Peak 1) 35.0-41.5 min; Isomer-B (Peak 2) 43.5-52.5min. Isomer-A. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 254 nm and 256 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=10 min, FlowRate=1 ml/min, Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 uM,R_(t)=7.86 min. LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column:Xterra MS C18 S7 3.0×50 mm; (ES+) m/z (M+H)⁺=673.56, HPLC R_(t)=1.637min. HPLC method: Solvent A=5% MeCN-95% H₂O-10 mM NH₄OAc, Solvent B=95%MeCN-5% H₂O-10 mM NH₄OAc, Start % B=0, Final % B=100, Gradient time=2min, Flow Rate=5 ml/min, Column: Phenomenex Lina C18 Sum 3.0×50 mm;(ES+) m/z (M+H)⁺=673.54, HPLC R_(t)=1.255 min. Optical rotation: 74.75°,(3.21 mg/ml MeOH, 589 nm, 50 mm cell).

Isomer-B. Analytical HPLC were performed by using Shimadzu-VP instrumentwith UV detection at 254 nm and 256 nm. Analytical HPLC method: SolventA=5% MeCÑ95% HÕ0.1% TFA, Solvent B=95% MeCÑ5% H2Õ0.1% TFA, Start % B=10,Final % B=100, Gradient time=10 min, Flow Rate=1 ml/min, Column: WatersSunfire C-18, 4.6×150 mm, 3.5 uM, Rt=8.35 min. LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1%TFA, Solvent B=90% MeO{tilde over (H)}10% H2Õ0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: XterraMS C18 S7 3.0×50 mm; (ES+) m/z (M+H)+=673.53, HPLC Rt=1.650 min. HPLCmethod: Solvent A=5% MeCÑ95% H2Õ10 mM NH4OAc, Solvent B=95% MeCÑ5% H2Õ10mM NH4OAc, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5ml/min, Column: Phenomenex Lina C18 Sum 3.0×50 mm; (ES⁺) m/z(M+H)+=673.54, HPLC Rt=1.263 min. Optical rotation: 75.36°, (3.29 mg/mlMeOH, 589 nm, 50 mm cell).

tert-Butyl13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

HATU (680 mg, 1.8 mmol) was added to a stirring solution of10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid (670 mg, 1.37 mmol) and 3-methyl-3,8-diazabicyclo[3.2.1]octane diHCl salt (560 mg, 2.81 mmol) in DMF (6 mL) and TEA (1.2 mL, 8.2 mmol)and the reaction was stirred for 30 min (complete by LCMS). The reactionmixture was diluted with water (˜35 mL) (precipitate formed) and stirredON. The precipitate was collected by filtration, flushed with water anddried under high vacuum at 55° C. to yield tert-butyl13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(775 mg, 1.30 mmol, 95% yield) as a light yellow solid. The material wasused without further purification. ¹HNMR (300 MHz, CDCl₃) δ ppm1.14-3.95 (m, 24H), 1.59 (s, 9H), 3.86 (s, 3H), 4.21-5.26 (m, 2H), 6.82(s, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.8, 2.6 Hz, 1H), 7.47 (d,J=8.8 Hz, 1H), 7.66 (dd, J=8.4, 1.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H),8.02 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode.

13-Cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid trifluoroacetate

tert-Butyl13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(300 mg, 0.504 mmol) was dissolved into DCE (5 mL) and then TFA (700 μl,9.09 mmol) was added (reaction became green) and the reaction wasstirred at rt for 1 h (70% conversion by LCMS). More TFA (700 μA, 9.09mmol) was added and the reaction was stirred 1 h (complete by LCMS). Thereaction mixture was concentrated on a rotary evaporator, diluted withdiethyl ether and reconcentrated twice to yield13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid trifluoroacetate (362 mg, 0.55 mmol, quant.) as a dark yellowsolid. Used without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ ppm1.06-2.13 (m, 21H), 2.68-2.86 (m, 1H), 3.36-3.50 (m, 2H), 3.90 (s, 3H),4.11-5.35 (m, 2H), 7.14 (s, 1H), 7.18-7.28 (m, 2H), 7.53 (d, J=8.4 Hz,1H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.21 (br s,1H), 9.55 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+).LC-MS retention time: 2.50 min; 538 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

tert-Butyl8-cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylate

Trimethylsulfoxonium iodide (375 mg, 1.69 mmol) was added in threeportions to s stirring slurry of a 60% NaH dispersion (68 mg, 1.7 mmol)in DMSO (1.5 mL) (foaming occurred). The reaction mixture was stirred 20min and then a solution of tert-butyl13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(438 mg, 0.735 mmol) in DMSO (2.5 mL) was added and the reaction wasstirred for 1 h (no desired product by LCMS). The reaction mixture washeated at 90° C. for 3 h (complete by LCMS), cooled to rt, quenched with0.25M aq. HCl (20 mL), and extracted with EtOAc (2×20 mL). The combinedorganic layers were washed with brine (20 mL), dried (MgSO₄), filteredand concentrated to yield 72009-057 as an orange oil. The oil was usedwithout further purification as starting material in the preparation of8-cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid trifluoroacetate. The compound was isolated as a mixture ofenantiomers. LC-MS retention time: 3.68 min; m/z 610 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was10% MeOH/90% H₂O/0.1% trifluoroacetic acid and solvent B was 10% H₂O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode.

8-Cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid trifluoroacetate

Starting material (448 mg, 0.735 mmol) was dissolved into DCE (6 mL) andthen TFA (1.5 mL, 19 mmol) was added (reaction became dark red) and thereaction was stirred at rt for 2 h (complete by LCMS). The reaction wasconcentrated on a rotary evaporator, diluted twice with diethyl etherand reconcentrated to an orange oil. The residue was slurried withdiethyl ether and the solids (360 mg yellow solid) were collected byfiltration and rinsed with hexanes. Addition solids (52 mg of a yellowsolid) were collected from the filtrate and rinsed with hexanes. Thecombined solids were shown to be8-cyclohexyl-11-methoxy-1a-43-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid trifluoroacetate (412 mg, 0.62 mmol, 84%). The compound wasisolated as a mixture of enantiomers and presents as a 1:5 mixture ofrotamers or atrope isomers. For major isomer: ¹HNMR (300 MHz, CDCl₃) δppm 0.81-1.01 (m, 2H), 1.13-2.65 (m, 18H), 2.62 (s, 3H) 2.69-3.70 (m,2H), 3.60 (d, J=15.4 Hz, 1H), 3.87 (s, 3H), 4.36-5.30 (m, 3H), 6.95 (dd,J=8.8, 2.2 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.75(d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.08 (s, 1H). LC-MS retentiontime: 3.24 min; 554 m/z (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C183.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode.

8-Cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide

CDI (21.3 mg, 0.131 mmol) was added to a stirring solution of8-cyclohexyl-11-methoxy-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid trifluoroacetate (56 mg, 0.10 mmol)) in THF (0.5 mL) and thereaction mixture was heated at 60° C. for 1.5 h. The reaction was cooledto rt and propane-1-sulfonamide (16 mg, 0.13 mmol) and then DBU (0.025mL, 0.15 mmol, as a 20% solution in THF) were added. The reaction wasstirred at rt for 1 h and more DBU (˜0.025 mL) was added. The reactionwas stirred 2 h at rt, heated at 60° C. for 1 h, and stirred ON at rt.More DBU (0.025 mL) and propane-1-sulfonamide (16.20 mg, 0.131 mmol)were added to the reaction mixture and was stirring continued at rt for3 days. The reaction was diluted with EtOAc (2 mL) and washed with 1MHCl (2 mL). The organic layer was concentrated to dryness with a streamof nitrogen, dissolved into MeOH (1.5 mL), filtered and purified bypreparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc) to yield8-cyclohexyl-11-methoxy-1a-43-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(9.0 mg, 0.014 mmol, 14% yield) as a yellow solid. The compound wasisolated as a mixture of enantiomers and presents as a 1:2 mixture ofrotamers or atrope isomers. ¹HNMR (500 MHz, CDCl₃) δ ppm −0.37-0.20 (m,0.33H), 0.24-0.29 (m, 0.33H), 0.89-3.03 (m, 31.33H), 3.54-3.64 (m, 2H),3.89 (s, 2H), 3.90 (s, 1H), 4.04-4.67 (m, 1H), 4.74 (d, J=14.7 Hz,0.33H), 5.19 (d, J=15.0 Hz, 0.67H), 6.93 (dd, J=8.6, 2.4 Hz, 0.33H),6.96 (dd, J=8.6, 2.4 Hz, 0.67H), 7.00 (d, J=2.4 Hz, 0.33H), 7.12 (d,J=2.4 Hz, 0.67H), 7.29 (d, J=8.6 Hz, 0.67H), 7.30 (d, J=8.6 Hz, 0.33H),7.55 (d, J=8.2 Hz, 0.33H), 7.64 (br d, J=8.2 Hz, 0.67H), 7.87 (d, J=8.2Hz, 0.67H), 7.88 (d, J=8.2 Hz, 0.33H), 7.98 (s, 1H). LC-MS retentiontime: 3.13 min; 659 m/z (MH+). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C183.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of mL/min,a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solventB, a gradient time of 4 min, a hold time of 1 min, and an analysis timeof 5 min where solvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acidand solvent B was 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS datawas determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid

Tetrabutylammoniumhydroxide (9.1 mL, 40% solution in water) was addeddropwise to a cooled solution (0° C., ice bath) containing dimethyl13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate and THF(463 mL). The solution was maintained with continued cooling for 50 min.and then concentrated to a volume of about 50 mL. The resultant solutionwas diluted with ethyl acetate (250 mL), washed with aq. HCl (0.5 N,3×150 mL), washed with brine (150 mL), dried (magnesium sulfate),filtered, and concentrated to afford a yellow solid. LCMS: retentiontime: 1.698 min. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% CH₃CN/95% H₂O/10 mM ammonium acetate and solvent B was5% H₂O/95% CH₃CN/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode: m/z 416 (MH⁺). ¹H NMR(300 MHz, DMSO-D6) δ ppm: 12.97 (s, 1H), 8.17 (m, 1H), 7.91 (m, 2H),7.63 (m, 5H), 5.56 (s, 1H), 4.51 (m, 1H), 3.89 (m, 3H), 2.80 (m, 1H),1.99 (m, 6H), 1.30 (m, 4H).

Methyl13-cyclohexyl-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

TBTU (115 mg, 0.361 mmol) was added at rt, in one portion, to a solutioncontaining13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid (100 mg, 0.241 mmol), DIEA (0.17 mL, 0.964 mmol),3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (115 mg, 0.289mmol), and DMF (2.4 mL). The solution was maintained for 18 h andconcentrated. The resultant residue was charged with dichloromethane (30mL), washed with water (4×15 mL), washed with brine (15 mL), dried(magnesium sulfate), filtered and concentrated to afford a yellow solidwhich was used without further purification in the next step. LCMS:retention time: 2.272 min LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 4 min, a hold time of 1 min, and an analysis time of 5min where solvent A was 5% CH₃CN/95% H₂O/10 mM ammonium acetate andsolvent B was 5% H₂O/95% CH₃CN/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode: m/z524 (MH⁺). Crude ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.19 (s, 1H), 7.92 (d,J=8.4 Hz, 1H), 7.77 (dd, J=8.78 Hz, J=1.46 Hz, 1H), 7.61 (m, 1H), 7.49(m, 3H), 6.96 (s, 1H), 5.2 (s, 1H), 4.41 (s, 1H), 2.81 (m, 4H), 2.51 (s,1H), 1.95 (m, 15H), 1.29 (m, 11H), 0.76 (m, 2H).

Methyl8-cyclohexyl-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylate

Sodium hydride (60% dispersion, 573 mg, 14.3 mmol) was added at rt to astirred suspension containing trimethylsulfoxonium iodide (3.15 g, 14.3mmol) in anhydrous DMSO (6.9 mL) under nitrogen. The resultant mixturewas stirred at rt for 1 h. Methyl13-cyclohexyl-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(1.5 g, 2.86 mmol) was then added in small portions. The suspension wasdiluted with DMSO (2 mL) and then heated with stirring at 90° C. for 1.5h. The reaction mixture was allowed to cool to rt and water was added (1mL). The mixture was poured into water (40 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(20 mL), dried (magnesium sulfate), filtered and concentrated to afforda yellow solid which was used without further purification. LCMS:retention time: 2.238 min LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 4 mL/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 4 min, a hold time of 1 min, and an analysis time of 5min where solvent A was 5% CH₃CN/95% H₂O/10 mM ammonium acetate andsolvent B was 5% H₂O/95% CH₃CN/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode:m/z538 (MH⁺).

8-cyclohexyl-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid

Boron tribromide (1.0 M in CH₂Cl₂, 9.6 mL) was added dropwise to acooled solution (˜20° C., dry ice/acetone) containing methyl8-cyclohexyl-1a-43-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylateand dichloromethane (17 mL). The mixture was stirred with continuedcooling for 10 min., removed from cooling, and stirred at ambienttemperature for 1.5 h. The solution was cooled again (0° C., ice bath)and quenched with water (2 mL). The resultant mixture was diluted withethyl acetate (50 mL) followed by slow addition of aqueous, saturatedsodium bicarbonate (50 mL), and stirred for 30 minutes. The resultingbiphasic mixture was partitioned, the organic layer washed with water(3×10 mL), washed with brine (10 mL), dried (magnesium sulfate),filtered and concentrated to afford a yellow solid. LCMS: retentiontime: 2.187 min LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% CH₃CN/95% H₂O/10 mM ammonium acetate and solvent B was5% H₂O/95% CH₃CN/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode: m/z 524 (MH⁺).

(1aR,12bS)-8-cyclohexyl-N-(isopropylsulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamideand(1aS,12bR)-8-cyclohexyl-N-(isopropylsulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide

EDCI (275 mg, 1.43 mmol) was added at rt, in one portion, to a solutioncontaining8-cyclohexyl-1a-43-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (500 mg, 0.955 mmol), DMAP (58 mg, 0.477 mmol), 2-isopropylsulfonamide (176 mg, 1.43 mmol) and dichloromethane (9.5 mL). Thesolution was maintained at rt for 24 h, diluted with additionaldichloromethane (50 mL), washed with aqueous saturated sodiumbicarbonate (2×20 mL), washed with water (20 mL), dried (magnesiumsulfate), filtered and concentrated. The resulting orange residue waspurified by preparative reverse phase HPLC to afford a yellow solid as aTFA salt. LCMS: retention time: 2.380 min LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% CH₃CN/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% CH₃CN/10 mM ammoniumacetate. MS data was determined using a Micromass Platform for LC inelectrospray mode: m/z 629 (MH⁺). Enantiomers were separated usingchiral HPLC on a ChiralPak AS-H, 5 micron, 4.6×250 mm column (12%MeOH/88% CO₂ mobile phase). Retention times: 12.60 min. and 19.05 min.NMR (300 MHz, MeOD) δ ppm: 8.01 (m, 2H), 7.65 (m, 2H), 7.47 (m, 3H),5.09 (m, 1H), 4.70 (s, 1H), 4.26 (m, 1H), 3.97 (m, 1H). 3.70 (m, 1H),3.56 (m, 0.5H), 3.44 (t, 2H), 3.30 (m 0.5H), 3.20-2.55 (overlappingseries of multiplets, 6H), 2.53-1.7 (overlapping series of multiplets,11H), 1.6-0 (overlapping series of multiplets, 12H).

(1aR,12bS)-8-cyclohexyl-N-(dimethylsulfamoyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamideand (1aS,12bR)-8-cyclohexyl-N-(dimethylsulfamoyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide

These compounds were prepared from8-cyclohexyl-1a-43-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid under similar conditions to those described for(1aR,12bS)-8-cyclohexyl-N-(isopropylsulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamideand(1aS,12bR)-8-cyclohexyl-N-(isopropylsulfonyl)-1a-43-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.The resulting yellow residue was purified by preparative reverse phaseHPLC to afford a yellow solid as a TFA salt. LCMS: retention time: 2.746min LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% CH₃CN/95% H₂O/10 mM ammonium acetate and solvent B was5% H₂O/95% CH₃CN/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode: m/z 630 (MH⁺).Enantiomers were separated using chiral HPLC on a ChiralPak AS-H, 5micron, 4.6×250 mm column (12% MeOH/88% CO₂ mobile phase). Retentiontimes: 13.16 min and 20.63 min. All of the compounds and examples whichfollow were analyzed by the following LC method: Column:PHENOMENNEX-LUNA 3.0×50 mm S10; Mobile Phase: (A) 10:90 methanol-water;(B) 90:10 methanol-water; Buffer: 0.1% TFA; Gradient Range: 0-100% B;Gradient Time: 2 min; Flow Rate: 4 mL/min; Analysis Time: 3 min;Detection: Detector 1:UV at 220 nm; Detector 2:MS (ESI+).

(+/−)-8-cyclohexyl-N-(N-cyclopropyl-N-methylsulfamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-N-methyl-5-carboxamide

Neat CDI (49 mg, 0.302 mmol) was added to stirred solution of mono acid(92 mg, 0.200 mmol) in an. THF (1 ml) and the mixture was heated at 50°C. for 30 min and then allowed to cool to rt. ThenN-cyclopropyl-N-methylsulfamide (45.1 mg, 0.300 mmol) and DBU (0.060 ml,0.400 mmol) were added consecutively. The mixture sonicated for 1-2 handthen stirred overnight at rt. Reaction was quenched with MeOH (0.5 ml)and then acidified with 1N HCl and extracted with EtOAc (2×25 mL),washed with water, brine and dried (Na₂SO₄). Crude product (123 mg) waspurified by silica gel flash chromatography (5% MeOH in DCM) to affordamide-ester as an off-white solid (101 mg). 1N NaOH (2 mL, 2.000 mmol)was added to stirred solution of the amide ester (98 mg, 0.166 mmol) inTHF-MeOH under nitrogen. The mixture was stirred at rt for 2 h and thenacidified with 1N HCl (3 ml), extracted with EtOAc (2×25 ml), washedwith water, brine and dried (MgSO4). Evaporation of solvents affordedamide-acid as an off-white solid (94 mg). Neat2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(53.5 mg, 0.167 mmol) was added to a stirred mixture of the amide-acid(74 mg, 0.128 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane, 2HCl (26.4mg, 0.128 mmol) and TEA (0.071 ml, 0.512 mmol) in DCM (2 ml) undernitrogen. The mixture was stirred at rt for 1 h and quenched with MeOH(0.5 ml) and then evaporated to dryness and purified by reverse-phaseHPLC to afford diamide and isolated in mono TFA salt form (61.3 mg) as abeige solid. LC/MS: Retention time: 1.857 min; m/e 686 (MH⁺). Theproduct was observed to exist as inter-converting rotamers by 1H NMR(500 MHz, CHLOROFORM-D) δ ppm 0.72-0.84 (m, J=1.83 Hz, 2H), 0.85-0.96(m, J=2.44 Hz, 2H), 1.19-1.31 (m, 1H), 1.33-1.48 (m, 2H), 1.50-1.62 (m,1H), 1.69-1.89 (m, 8H), 1.92-2.23 (m, 10H), 2.56-2.69 (m, 2H), 2.77-2.90(m, 1H), 2.90-3.02 (m, 1H), 3.04-3.14 (m, 4H), 3.11-3.54 (m, 1H),3.60-3.71 (m, J=15.26 Hz, 1H), 3.82-3.96 (m, 3H), 5.06-5.22 (m, 1H),6.92-7.01 (m, J=8.55, 2.44 Hz, 1H), 7.07-7.14 (m, J=2.14 Hz, 1H),7.27-7.33 (m, J=8.55 Hz, 1H), 7.40-7.49 (m, 1H), 7.86-7.94 (m, J=8.24Hz, 1H), 7.98-8.06 (m, 1H).

Neat potassium thioacetate (1.371 g, 12.00 mmol) was added to a stirredsolution of 2-bromo-1,1-difluoroethane (1.45 g, 10.00 mmol) in DMF (6ml) and the mixture stirred overnight. Product was extracted with ether(2×25 ml), washed with water, brine and dried (Na2SO4). Evaporation ofether gave the intermediate, HCF2CH2SCOCH3 (1.18 g, 84.3%) as a lightbrown oil which was dissolved in DCM (10 ml) and mixed with water (10ml). Chlorine gas was bubbled into stirred cold (0° C.) two-phasesolution of HCF2CH2SCOCH3 (1.18 g) until permanent green color ispersistent and maintained for 1-2 h. DCM layer was separated and washedwith 10% NaHSO3, water, brine and dried (MgSO4). Evaporation of DCM gavethe intermediate HCF2CH2SO2Cl (1.13 g) as a light yellow oil which wastreated with an. NH3 (0.5 M in dioxane, 40 ml) at 0° C. for 1 h.Precipitated NH4Cl was filtered through a plug of silica gel and thenfiltrate was evaporated to dryness to afford2,2-difluoroethanesulfonamide as a light-yellow oil (736 mg). 1H NMR(400 MHz, CHLOROFORM-D) δ ppm −2.04 (brd s, 2H), 3.78 (m, 2H), 5.23 (m,1H).

(+/−)-8-cyclohexyl-N-(2,2-difluoroethylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Neat CDI (24.60 mg, 0.152 mmol) was added to a stirred solution ofacid-amide (56 mg, 0.101 mmol) in an. THF (1 ml) and the mixture washeated at 50° C. for 30 min and allowed to cooled to rt. Then2,2-difluoroethanesulfonamide (29.4 mg, 0.202 mmol) and DBU (0.046 ml,0.303 mmol) were added consecutively and the mixture was sonicated 2-3h. Rxn was quenched with methanol (1 ml) and acidified with few drops ofTFA and purified by reverse-phase prep. HPLC to afford the product andisolated in mono TFA salt as a beige solid. LC/MS: Retention time: 2.861min; m/e 681 (MH⁺). The product was observed to exist asinter-converting rotamers by 1H NMR (500 MHz, CHLOROFORM-D) δ ppm1.12-1.31 (m, J=4.27 Hz, 3H), 1.32-1.55 (m, 4H), 1.63-1.87 (m, 3H),1.87-2.11 (m, 5H), 2.14-2.34 (m, 1H), 2.34-2.90 (m, 8H), 2.91-3.06 (m,2H), 3.35-3.54 (m, 1H), 3.56-3.70 (m, J=14.95 Hz, 1H), 3.83-3.95 (m,3H), 3.93-4.14 (m, 1H), 4.14-4.34 (m, 1H), 4.36-4.64 (m, 1H), 5.11-5.30(m, 1H), 6.11-6.41 (m, 1H), 6.94-7.02 (m, J=8.39, 2.59 Hz, 1H),7.08-7.15 (m, J=2.44 Hz, 1H), 7.27-7.33 (m, 1H), 7.56-7.72 (m, 1H),7.89-7.97 (m, J=8.55 Hz, 1H), 7.99-8.08 (m, 1H).

A solution of methanesulfonyl chloride (1.714 ml, 22.00 mmol) in DCM (5ml) was added dropwise to a stirred cold (0° C.) solution of3-fluoropropan-1-ol (1.562 g, 20 mmol) and TEA (3.35 ml, 24.00 mmol) inDCM (20 ml). The mixture was stirred at 0-5° C. for ˜2 h and washed withwater, satd. NaHCO₃, water, brine and dried (MgSO₄). Evaporation of DCMgave 3-fluoropropyl methanesulfonate as a colorless oil (2.92 g, 93.6%).Neat potassium thioacetate (2.74 g, 24.00 mmol) was added to a stirredsolution of 3-fluoropropyl methanesulfonate (2.9 g) in DMSO (20 ml) andthe mixture stirred overnight. Product was extracted with ether (2×25ml), washed with water, brine and dried (MgSO4). Evaporation of ethergave S-3-fluoropropyl ethanethioate as a light brown oil. Chlorine gaswas bubbled into cold (−10° C.) stirred two-phase solution ofS-3-fluoropropyl ethanethioate (1.0 g, 7.34 mmol) in DCM (5 ml) andWater (5.00 ml) until green color appeared in aqueous phase andmaintained for 1-2 h. Layers separated and aq. layer re-extracted withDCM (2×10 ml). Combined DCM extracts were washed with 10% NaHSO3solution, water, brine and dried (MgSO4). Evaporation of DCM gave theintermediate, 3-fluoropropane-1-sulfonyl chloride as a light brown oil(405 mg, 34%) which was treated with an. NH3 solution (10 ml, 0.5M indioxane) and stirred for 30-45 min. Precipitated NH4Cl was filtered offand the filtrate was evaporated to dryness to afford3-fluoropropane-1-sulfonamide as a light brown oil (265 mg).

(+/−)-8-cyclohexyl-N-(3-fluoropropylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Neat CDI (24.60 mg, 0.152 mmol) was added to a stirred solution ofacid-amide (56 mg, 0.101 mmol) in an. THF (1 ml) and the mixture washeated at 50° C. for 30 min and allowed to cool to rt. Then3-fluoropropane-1-sulfonamide (28.6 mg, 0.202 mmol) and DBU (0.046 ml,0.303 mmol) were added consecutively and the mixture was sonicated 2-3h. Rxn was quenched with methanol (1 ml) and acidified with few drops ofTFA and purified by reverse-phase prep. HPLC to afford the product andisolated in mono TFA salt form as a beige solid. LC/MS: Retention time:2.835 min; m/e 677 (MH⁺). The product was observed to exist asinter-converting rotamers by 1H NMR (400 MHz, CHLOROFORM-D) δ ppm0.13-0.37 (m, 1H), 1.08-1.31 (m, 2H), 1.31-1.61 (m, 4H), 1.70-1.86 (m,2H), 1.86-2.11 (m, 6H), 2.13-2.36 (m, 3H), 2.38-2.68 (m, 1H), 2.69-3.01(m, 3H), 3.03-3.34 (m, J=68.99 Hz, 1H), 3.35-3.84 (m, 7H), 3.84-3.95 (m,3H), 3.95-4.12 (m, 1H), 4.44-4.57 (m, J=5.20, 5.20, 5.20 Hz, 2H),4.58-4.72 (m, J=5.29, 5.29 Hz, 2H), 5.03-5.30 (m, 1H), 6.91-7.02 (m,1H), 7.08-7.15 (m, J=2.27 Hz, 1H), 7.27-7.35 (m, 1H), 7.52-7.69 (m,J=31.98 Hz, 1H), 7.85-7.97 (m, J=7.93, 7.93 Hz, 1H), 8.04-8.13 (m, 1H).

(−)-8-cyclohexyl-N-((2S,6R)-propane-2-sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

To a mixture of acid-amide (341 mg, 0.62 mmol) and3-methyl-3,8-diazabicyclo[3.2.1]octane, 2HCl (148 mg, 0.743 mmol) indichloromethane (5 ml) was added TEA (0.259 ml, 1.858 mmol) and HBTU(282 mg, 0.743 mmol). The mixture was stirred at room temperatureovernight. Diluted with EtOAc (150 ml) and washed with aqueous 0.3 MNaHCO3 solution (2×10 mL), water brine, dried (MgSO4), removed thesolvent and purified by Biotage 25M column (MeOH/DCM:0 to 25%). Thecollection was dissolved in 100 mL EtOAc and washed with aqueous HCl(3×20 ml, 0.1M), 0.3 M NaHCO3 solution, brine, dried (MgSO4), removedthe solvent to afford the product as a yellow solid (0.280 g, 68%).LC-MS retention time: 3.105; MS m/z (M+H) 659. The product was observedto exist as inter-converting rotamers by 1H NMR (400 MHz, MeOD) δ ppm1.37 (10H, m), 2.37 (15H, m), 3.76 (8H, m), 3.88 (3H, m), 4.36 (2H, m),5.06 (1H, m), 6.97 (1H, m), 7.17 (1H, d, J=1.76 Hz), 7.27 (1H, m), 7.55(1H, d, J=8.56 Hz), 7.85 (1H, m), 7.98 (1H, br. s.).

8-cyclohexyl-N-(methylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Step 1: The racemate was separated by using ChiralCel OJ-H column (15%EtOH/85% CO₂) to afford optically pure enantiomers. Step 2: Anenantiomer was hydrolyzed to afford the corresponding acid: LC-MSretention time: 3.426; MS m/z (M+H) 523. Step 3:Amide derivative waspurified by prep. HPLC and isolated as a TFA salt. LC-MS retention time:2.913; MS m/z (M+H) 631. The product was observed to exist asinter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36(6H, m), 1.7-3.2 (16H, m), 3.48 (2H, m), 3.43 (3H, s), 3.67 (2H, m),3.91 (3H, m), 4.59 (2H, m), 5.24 (1H, m), 6.96 (1H, m), 7.12 (1H, d,J=2.52 Hz), 7.27 (1H, m), 7.62 (1H, m), 7.90 (1H, m), 8.22 (1H, br. s.).

(+/−)-8-cyclohexyl-N-(2,2-dimethylpropane-1-sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The starting material was purified by Prep HPLC and isolated as a TFAsalt. LC-MS retention time: 3.263 min; MS m/z (M+H) 687. The product wasobserved to exist as inter-converting rotamers. 1H NMR (500 MHz,CHLOROFORM-d) δ ppm 1.21 (9H, s), 1.41 (5H, m), 1.99 (11H, m), 2.40-4.50(14H, m), 3.89 (3H, s), 5.17 (1H, m), 6.97 (1H, m), 7.11 (1H, d, J=2.44Hz), 7.30 (1H, m), 7.51 (1H, br. s.), 7.89 (1H, d, J=7.93 Hz), 8.07 (1H,m).

(+/−)-8-cyclohexyl-N-cyclobutanesulfonyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time:3.138 min; MS m/z (M+H) 671. The product was observed toexist as inter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.37 (7H, m), 2.01 (10H, m), 2.63 (14H, m), 3.46 (1H, d), 3.62 (1H, d,J=15.11 Hz), 3.89 (3H, s), 4.59 (2H, m), 5.18 (1H, m), 6.97 (1H, m),7.11 (1H, d, J=2.52 Hz), 7.29 (1H, m), 7.62 (1H, m), 7.89 (1H, m), 8.05(1H, s).

(+/−)-8-cyclohexyl-N-cyclopentanesulfonyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time: 3.190 min; MS m/z (M+H) 685.

(+/−)-8-cyclohexyl-N-cyclohexanesulfonyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time: 3.261 min; MS m/z (M+H) 699. The product was observed toexist as inter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.61 (22H, m), 2.86 (12H, m), 3.48 (1H, m), 3.63 (1H, d, J=15.11 Hz),3.74 (1H, m), 3.89 (3H, s), 4.56 (2H, m), 5.24 (1H, m), 6.98 (1H, m),7.11 (1H, d, J=2.27 Hz), 7.30 (1H, m), 7.60 (1H, m), 7.90 (1H, m), 8.08(1H, br. s.).

(+/−)-8-cyclohexyl-N-2-methylpropane-1-sulfonyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time: 3.210 min; MS m/z (M+H) 673. The product was observed toexist as inter-converting rotamers. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm1.14 (6H, m), 1.32 (3H, m), 1.46 (4H, m), 1.62 (1H, m), 1.80 (3H, m),2.07 (8H, m), 2.33 (2H, m), 2.68 (1H, m), 2.95 (5H, m), 3.33 (3H, m),3.49 (2H, m), 3.66 (1H, d, J=15.26 Hz), 3.89 (3H, s), 4.21 (1H, m), 4.65(1H, m), 5.15 (0H, d, J=14.95 Hz), 7.02 (1H, dd, J=8.55, 2.44 Hz), 7.18(0H, d, J=1.83 Hz), 7.32 (1H, d, J=8.55 Hz), 7.58 (0H, m), 7.91 (1H, m),7.99 (0H, br. s.).

(+/−)-8-cyclohexyl-N-(2-methylpropane-2-sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and further purified by prep TLC.LC-MS retention time: 3.226 min; MS m/z (M+H) 685.

(+/−)-8-cyclohexyl-N-(butanesulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time:3.245 min; MS m/z (M+H) 673. The product was observed toexist as inter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm0.94 (3H, t, J=7.30 Hz), 1.24 (2H, m), 1.46 (6H, m), 1.90 (14H, m), 2.72(4H, m), 3.02 (2H, m), 3.41 (1H, m), 3.62 (3H, m), 3.88 (3H, s), 4.39(2H, m), 5.18 (1H, m), 6.98 (1H, m), 7.11 (1H, d, J=2.52 Hz), 7.30 (1H,m), 7.62 (1H, m), 7.90 (1H, m), 8.05 (1H, s).

(+/−)-8-cyclohexyl-N-[(+/−)-(trifluoromethanesulfonyl)]-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time: 3.203 min; MS m/z (M+H) 685. The product was observed toexist as inter-converting rotamers. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.34 (5H, m), 2.05 (8H, m), 3.02 (12H, m), 3.59 (1H, d, J=15.11 Hz),3.89 (3H, s), 4.51 (2H, m), 5.16 (1H, m), 6.98 (1H, m), 7.11 (1H, d,J=2.27 Hz), 7.29 (1H, d, J=8.56 Hz), 7.58 (1H, m), 7.86 (1H, m), 8.05(1H, br. s.).

(+/−)-8-cyclohexyl-N-(pentane-3-sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

The product was purified by Prep HPLC and isolated as a TFA salt. LC-MSretention time: 3.250 min; MS m/z (M+H) 687. The product was observed toexist as inter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.39 (37H, m), 2.84 (2H, m), 3.28 (0H, br. s.), 3.59 (0H, m), 3.73 (0H,m), 3.89 (3H, m), 4.23 (2H, m), 5.18 (0H, br. s.), 6.99 (1H, m), 7.11(1H, br. s.), 7.25 (1H, m), 7.69 (0H, br. s.), 7.86 (2H, br. s.).

8-cyclohexyl-N-(cyclopropylsulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Step 1: The racemic starting material was separated into optically pureenantiomers by using ChiralPak AS-H, 30×250 mm, 5 μm column (15%EtOH/85% CO₂) to afford (−)-enantiomer (first peak) and (+)-enantiomer(second peak). Step 2:To a solution of one isomer (0.397 g, 0.706 mmol)in THF (4 ml) and MeOH (4 ml) was added 1N NaOH (2 ml, 2.000 mmol). Themixture was stirred at room for 2 h. Diluted with EtOAc, washed withcold HCl (1N), brine, dried (MgSO₄), and removed the solvent in vacuo toafford compound acid-amide as a yellow solid (0.387 g, 100%). LC-MSretention time: 3.473 min; MS m/z (M+H) 549. Step 3: The diamide waspurified and isolated as TFA salt. LC-MS retention time: 2.991 min; MSm/z (M+H) 657.

8-cyclohexyl-N-cyclobutanesulfonyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Step 1:To a suspension of compound diester (0.63 g, 1.189 mmol) in DCM(1 mL) was added TFA (1 mL, 12.98 mmol), stirred at r.t. for 2.5 h,removed the solvents in vacuo to afford compound mono acid as a darkbrown solid. LC-MS retention time: 3.686; MS m/z (M+H) 474. Step 2:To amixture of compound mono acid (100 mg, 0.211 mmol),cyclobutanesulfonamide (57.1 mg, 0.422 mmol), DMAP (103 mg, 0.845 mmol),and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.7mg, 0.317 mmol) in a vial was added DCM (1 ml). The mixture was stirredat r.t. overnight and purified by Biotage 25S column (MeOH/DCM: 0 to25%) to afford compound amide-ester as a yellow solid (0.086 g, 68%).LC-MS retention time: 3.528; MS m/z (M+H) 591. Step 3:To a solution ofthis compound (86 mg, 0.146 mmol) in THF (2 ml) and MeOH (1 ml) wasadded 1N NaOH (1 ml, 1.0 mmol). The mixture was stirred at room for 2 h.Diluted with EtOAc, washed with cold HCl (1N), brine, dried (MgSO₄), andremoved the solvent in vacuo to afford mono acid as a brown solid. LC-MSretention time: 3.463; MS m/z (M+H) 563. Step 4: The diamide waspurified by prep HPLC and isolated as TFA salt. LC-MS retention time:3.128; MS m/z (M+H) 671.

To a solution of chlorosulfonyl isocyanate (1.230 ml, 14.13 mmol) in DCM(10 ml) was added tert-BuOH (1.351 ml, 14.13 mmol) at 0° C. dropwise.The mixture was stirred at room temperature for 1 h and added a solutionof N-methylpropan-2-amine (1.57 ml, 14.13 mmol) and TEA (2.167 ml, 15.54mmol) in DCM (3 ml) at 0° C. The mixture was stirred at room temperaturefor 2 h and diluted with EtOAc, washed with cold 1N HCl, brine, dried(MgSO₄), removed the solvent and purified by Biotage 40M column(EtOAc-MeOH (90-10)/hexane 5% to 100%) to afford a colorless gel (2.3 g,64.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J=6.55 Hz, 6H)1.49 (s, 9H) 2.90 (s, 3H) 4.05-4.26 (m, 1H) 7.02 (br. s., 1H). Totert-butyl N-isopropyl-N-methylsulfamoylcarbamate (2.3 g, 9.12 mmol) wasadded cold HCl (dioxane, 6 mL, 24.00 mmol) and stirred at roomtemperature for 2 h, removed the solvent to affordN-isopropyl-N-methylsulfamide as a light tan solid (1.38 g, 99%). 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.80 Hz, 5H) 2.72 (s, 3H) 4.16(dt, J=13.53, 6.70 Hz, 1H) 4.43 (br. s., 1H).

(+/−)-8-cyclohexyl-N-(N-isopropyl-N-methysulfomoyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Step 1: To a solution of compound acid-ester (0.25 g, 0.544 mmol) in THF(4 ml) was added CDI (0.132 g, 0.816 mmol) and heated at 50° C. for 0.5h. Cooled down and added, N-isopropyl-N-methylsulfamide (0.083 g, 0.544mmol) and DBU (0.123 ml, 0.816 mmol). The mixture was stirred at roomtemperature overnight. Another portion of N-isopropyl-N-methylsulfamide(0.050 g, 0.326 mmol) and DBU (0.123 ml, 0.816 mmol) were added. Themixture was stirred for additional day and few drops of MeOH were addedand diluted with EtOAc, washed with cold HCl (1N), brine, dried (MgSO₄),and purified by Biotage 25 M column [EtOAc-MeOH (90-10)/hexane: 5% to100%] to afford mono amide as a colorless solid (0.261 g, 81%). LC-MSretention time: 3.635 min; MS m/z (M+H) 594. H NMR observed existingrotamers. Step 2: To a solution of compound mono amide (0.258 g, 0.435mmol) in THF (4 ml) and MeOH (2 ml) was added NaOH (2 ml, 2.000 mmol).The mixture was stirred at r.t. for 2 h, diluted with EtOAc, washed withcold HCl (1N), brine, dried (MgSO₄), and removed the solvent to affordamide-acid (0.22 g, 87%). LC-MS retention time: 3.608 min; MS m/z (M+H)580. The amide-acid was observed to exist as inter-converting rotamers.H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, J=6.30 Hz, 1H) 1.08-2.15(m, 17H) 2.63-2.80 (m, 1H) 2.84-2.96 (m, 1H) 3.04 (s, 3H) 3.84 (s, 3H)4.03 (d, J=14.86 Hz, 1H) 4.22-4.41 (m, 1H) 5.35 (d, J=15.11 Hz, 1H) 6.86(dd, J=8.44, 2.39 Hz, 1H) 6.98 (d, J=2.27 Hz, 1H) 7.20 (d, J=8.56 Hz,1H) 7.67 (d, J=8.31 Hz, 1H) 7.81-7.89 (m, 1H) 8.10 (s, 1H). Step 3: Thediamide was purified and isolated as TFA salt LC-MS retention time:3.146 min; MS m/z (M+H) 688. The diamide was observed to exist asinter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d)₈ ppm 1.14-1.18(m, 6H) 1.19-2.12 (m, 16H) 2.19-3.77 (m, 9H) 2.95 (s, 3H) 3.89 (s, 3H)3.95-5.02 (m, 4H) 5.03-5.24 (m, 1H) 6.97 (dd, J=8.81, 2.77 Hz, 1H) 7.11(d, J=2.52 Hz, 1H) 7.28 (d, J=8.56 Hz, 1H) 7.40-7.64 (m, 1H) 7.88 (d,J=8.31 Hz, 1H) 8.07 (br. s., 1H).

(+)-8-cyclohexyl-N-(propane-2-sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide

Step 1: To a solution of compound amide-ester (0.276 g, 0.489 mmol) inTHF (4 ml) and MeOH (2 ml) was added 1N NaOH (1.955 ml, 1.955 mmol). Themixture was stirred at room for 4 h. Diluted with EtOAc, washed withcold HCl (1N), brine, dried (MgSO₄), and removed the solvent in vacuo toafford the amide-acid as a yellow solid (0.269 g. 100%). LC-MS retentiontime: 3.480 min; MS m/z (M+H) 551. This compound was observed to existas inter-converting rotamers. 1H NMR (400 MHz, MeOD) δ ppm 1.33 (10H,m), 1.71 (3H, m), 2.01 (6H, m), 2.80 (2H, m), 3.40 (1H, d, J=15.11 Hz),3.86 (3H, s), 3.97 (1H, m), 5.42 (1H, d, J=14.60 Hz), 6.96 (1H, m), 7.18(1H, s), 7.26 (1H, m), 7.52 (1H, d, J=8.31 Hz), 7.85 (1H, m), 8.27 (1H,s). Step 2: The diamide was purified and isolated as TFA salt. LC-MSretention time: 3.146 min; MS m/z (M+H) 688. The diamide was observed toexist as inter-converting rotamers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.31 (13H, m), 2.14 (17H, m), 2.79 (1H, m), 2.95 (1H, s), 3.58 (1H, d,J=15.11 Hz), 3.89 (3H, m), 4.04 (1H, s), 4.41 (1H, s), 5.17 (1H, m),6.95 (1H, m), 7.11 (1H, s), 7.29 (1H, m), 7.72 (1H, s), 7.91 (2H, m).

We claim:
 1. A composition comprising a compound of formula I, apharmaceutically acceptable carrier, and at least one additionalcompound having therapeutic benefits for HCV

where: R¹ is CO₂R⁵ or CONR⁶R⁷; R² is

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, alkoxy, orhaloalkoxy; R⁴ is cycloalkyl; R⁵ is hydrogen or alkyl; R⁶ is hydrogen,alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)₂NSO₂, or) (R¹⁰)SO₂;R⁷ is hydrogen or alkyl; R⁸ is hydrogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl,alkoxycarbonyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂, aminocarbonyl,(alkylamino)carbonyl, (dialkylamino)carbonyl, benzyl, benzyloxycarbonyl,or pyridinyl; R⁹ is hydrogen, alkyl, or cycloalkyl; and R¹⁰ isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, or homomorpholinyl and is substitutedwith 0-3 alkyl substituents; or a pharmaceutically acceptable saltthereof; and where the additional compound having therapeutic benefitsfor HCV is selected from the group consisting of interferons,cyclosporine, interleukins, HCV metalloprotease inhibitors, HCV serineprotease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors,HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assemblyinhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5Bprotein inhibitors, and HCV replicon inhibitors.
 2. A method of treatinghepatitis C infection comprising administering a therapeuticallyeffective amount of a compound of formula I and at least one additionalcompound having therapeutic benefits for HCV to a patient

where: R¹ is CO₂R⁵ or CONR⁶R⁷; R² is

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, alkoxy, orhaloalkoxy; R⁴ is cycloalkyl; R⁵ is hydrogen or alkyl; R⁶ is hydrogen,alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)₂NSO₂, or (R¹⁰)SO₂; R⁷is hydrogen or alkyl; R⁸ is hydrogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl,alkoxycarbonyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂, aminocarbonyl,(alkylamino)carbonyl, (dialkylamino)carbonyl, benzyl, benzyloxycarbonyl,or pyridinyl; R⁹ is hydrogen, alkyl, or cycloalkyl; and R¹⁰ isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, or homomorpholinyl and is substitutedwith 0-3 alkyl substituents; or a pharmaceutically acceptable saltthereof; and where the additional compound having therapeutic benefitsfor HCV is selected from the group consisting of interferons,cyclosporine, interleukins, HCV metalloprotease inhibitors, HCV serineprotease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors,HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assemblyinhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5Bprotein inhibitors, and HCV replicon inhibitors.